Type 2 cytokine receptor and nucleic acids encoding same

ABSTRACT

The present invention provides novel isolated CRF2-13 polynucleotides and polypeptides encoded by the CRF2-13 polynucleotides. Also provided are the antibodies that immunospecifically bind to a CRF2-13 polypeptide or any derivative (including fusion derivative), variant, mutant or fragment of the CRF2-13 polypeptide, polynucleotide or antibody. The invention additionally provides methods in which the CRF2-13 polypeptide, polynucleotide and antibody are utilized in the detection and treatment of a broad range of pathological states, as well as to other uses.

RELATED APPLICATION

[0001] This application claims priority to U.S. S No. 60/332,366, filedNov. 9, 2001. The contents of this application are incorporated hereinby reference in their entirety.

FIELD OF THE INVENTION

[0002] The invention relates generally to nucleic acids and polypeptidesand more specifically to nucleic acids and polypeptides encoding type IIcytokine receptors, as well as vectors, host cells, antibodies andrecombinant methods for producing the polypeptides and polynucleotides.

BACKGROUND OF THE INVENTION

[0003] Cytokines such as interferons are soluble proteins that influencethe growth and differentiation of many cell types. Cytokines exert theireffects through cytokine receptors, which are located on the surface ofcells responsive to the effects of cytokines. Cytokine receptors arecomposed of one or more integral membrane proteins that bind thecytokine with high affinity and transduce this binding event to the cellthrough the cytoplasmic portions of the receptor subunits.

[0004] Cytokine receptors have been grouped into several classes on thebasis of similarities in their extracellular ligand binding domains. Forexample, the receptor chains responsible for binding and/or transducingthe effect of interferons cytokine are members of the type II cytokinereceptor family (CRF2), based upon the presence of a characteristic200-250 residue extracellular domain.

[0005] Members of the CRF2 family have been reported to act as receptorsfor a variety of cytokines, including interferon alpha, interferon beta,interferon gamma, IL-10, IL-20, and IL-22. Recently identified membersof the CRF2 family are candidate ligands for the IL-10-like moleculesIL-19, AK155 and mda-7.

[0006] The demonstrated in vivo activities of these interferonsillustrate the clinical potential of, and need for, other cytokines,cytokine agonists, and cytokine antagonists.

SUMMARY OF THE INVENTION

[0007] The invention is based, in part, upon the discovery ofpolynucleotide sequences encoding CRF2-13, novel member of the CRF2family.

[0008] Accordingly, in one aspect, the invention provides an isolatednucleic acid molecule that includes the sequence of SEQ ID NO:1, or afragment, homolog, analog or derivative thereof. The nucleic acid caninclude, e.g., a nucleic acid sequence encoding a polypeptide at least70%, e.g., 80%, 85%, 90%, 95%, 98%, or even 99% or more identical to apolypeptide that includes the amino acid sequences of SEQ ID NO:2. Thenucleic acid can be, e.g., a genomic DNA fragment, or a cDNA molecule.

[0009] Preferably, the isolated nucleic acid molecule encodes apolypeptide comprising an amino acid sequence at least 85% identical toamino acids 21-520 of SEQ ID NO:2. More preferably, the encodedpolypeptide is at least 90%, 95%, 98%, 99% identical to amino acids21-520 of SEQ ID NO:2. In some embodiments, the encoded polypeptideincludes amino acids 21-520 of SEQ ID NO:2. For example, the encodedpolypeptide in some embodiments includes amino acids 1-520 of SEQ IDNO:2. An example of such an isolated nucleotide is a nucleic acidmolecule that includes nucleotides 1-1563 of SEQ ID NO:1.

[0010] The invention additionally includes a vector comprising theisolated nucleic acid molecule that encodes a polypeptide comprising anamino acid sequence at least 85% identical to amino acids 21-520 of SEQID NO:2, as well as a cell that includes this vector. Also within theinvention is a pharmaceutical composition that includes the isolatednucleic acid molecule encoding a polypeptide comprising an amino acidsequence at least 85% identical to amino acids 21-520 of SEQ ID NO:2,along with a pharmaceutically acceptable carrier.

[0011] In some embodiments, the nucleic acid molecule encodes apolypeptide with an amino acid sequence having one or more substitutionsrelative to the amino acid sequence of amino acids 21-520 of SEQ IDNO:2. In some embodiments, the nucleic acid molecule hybridizes understringent conditions to a nucleic acid sequence complementary to anucleic acid molecule comprising SEQ ID NO:1. In addition, or in thealternative, the encoded polypeptide binds specifically to a polypeptideligand.

[0012] Also within the invention is are isolated nucleic acids encodinga polypeptide of at least 499 amino acids, wherein the nucleic acidhybridizes under low stringency, moderate stringency, and/or highstringency conditions to SEQ ID NO:1.

[0013] In another aspect, the invention provides a substantiallypurified polypeptide that includes an amino acid sequence at least 85%identical to the amino acid sequence of amino acids 21-520 of SEQ IDNO:2. In some embodiments, the polypeptide is at least 90%, 95%, 97%,98% or 99% or more identical to the amino acid sequence of SEQ ID NO:1.In some embodiments, the polypeptide differs by one or moresubstitutions from amino acids 21-520 of SEQ ID NO:2. In otherembodiments, the polypeptide includes amino acids 21-520 of SEQ ID NO:2.

[0014] Also within the invention is a pharmaceutical composition thatincludes an amino acid sequence at least 85% identical to the amino acidsequence of amino acids 21-520 of SEQ ID NO:2, and a pharmaceuticallyacceptable carrier.

[0015] Also within the invention is a polypeptide at least 85% identicalto amino acids 21-230 of SEQ ID NO:2. For example, the polypeptide canbe at least 95%, 97%, 98%, or 99% or more identical to amino acids21-230 of SEQ ID NO:2. In some embodiments, the polypeptide differs byone or more substitutions from amino acids 21-230 of SEQ ID NO:2. Inother embodiments, the polypeptide includes amino acids 21-230 of SEQ IDNO:2.

[0016] Also provided by the invention is a fusion polypeptide comprisinga CRF2-13 polypeptide operably linked to a non-CRF2-13 polypeptide. Insome embodiments, the CRF2-13 polypeptide includes amino acids 21-520 ofSEQ ID NO:2. For example, the CRF2-13 polypeptide can includes aminoacids 21-230 of SEQ ID NO:2. In some embodiments, the CRF2-13 is atleast 499 amino acids in length and is encoded by a nucleic acid thathybridizes under low, moderate, and/or high stringency conditions to SEQID NO:1.

[0017] The non-CRF2-13 polypeptide can include, e.g., an Fc region of animmunoglobulin molecules or a FLAG epitope, a HIS tag, and a MYC tag.

[0018] Also within the invention is a pharmaceutical composition thatincludes a fusion polypeptide with CRF2-13 polypeptide operably linkedto a non-CRF2-13 polypeptide, along a pharmaceutically acceptablecarrier.

[0019] Also provided by the invention is an antibody that binds to apolypeptide that includes a CRF2-13 polypeptide sequence (e.g., some orall of the amino acid sequence of SEQ ID NO:2). In some embodiments, theantibody neutralizes binding of a CRF2-13 polypeptide to a CRF2-13ligand. The antibody can be, e.g., a polyclonal antibody or a monoclonalantibody. The monoclonal antibody can be, e.g, a murine monoclonalantibody, or a humanized monoclonal antibody.

[0020] Also provided by the invention is a kit comprising in one or morecontainers a compound selected from the group consisting of an CRF2-13nucleic acid, an CRF2-13 polypeptide and an antibody to an CRF2-13polypeptide. The kit may optionally include directions for use. In someembodiments the compound is provided with a pharmaceutically acceptablecarrier.

[0021] Also provided by the invention is a method of producing a CRF2-13polypeptide, culturing a cell including a nucleic acid encoding aCRF2-13 polypeptide under conditions allowing for expression of apolypeptide encoded by the nucleic acid.

[0022] In a further aspect the invention provides a method of detectingthe presence of a CRF2-13 nucleic acid molecule in a biological sample.The method includes contacting the sample with a nucleic acid probe; andidentifying the bound probe, if present, thereby detecting the presenceof CRF2-13 nucleic acid molecule in the sample.

[0023] In some embodiments, the CRF2-13 nucleic acid molecule isdetected in a PCR reaction using primers (GCTGCAGGCCGCTCCAGGGAGGCCCCG;(SEQ ID:23) and (CCAGGTATTCGGACTCCACCCAGGGGGAC (SEQ ID NO:24).

[0024] Also provided by the invention is a method of detecting thepresence of a CRF2-13 polypeptide in a sample by contacting the samplewith a compound that selectively binds to the CRF2-13 polypeptide underconditions allowing for formation of a complex between the polypeptideand the compound and detecting the complex, if present, therebyidentifying the polypeptide in the sample.

[0025] In another aspect, the invention includes a method of modulatingthe activity of a CRF2-13 polypeptide by contacting a cell samplecomprising the polypeptide with a compound that binds to the polypeptidein an amount sufficient to modulate the activity of the polypeptide. Thecompound can be, e.g., a soluble CRF2-13 polypeptide inhibitor. In someembodiments, the soluble CRF2-13 inhibitor includes a polypeptide atleast 85% homologous to amino acids 21-260 of SEQ ID NO:2.

[0026] Also provided by the invention is a method for screening for amodulator of activity or of latency or predisposition to acytokine-mediated immune disorder. The method includes contacting a testcompound with a CRF2-13 polypeptide; and determining if the testcompound binds to the CRF2-13 polypeptide. Binding of the test compoundto the polypeptide indicates the test compound is a modulator ofactivity or of latency or predisposition to a cytokine-mediated immunedisorder.

[0027] In another aspect, the invention provides a method for screeningfor a modulator of activity or of latency or predisposition to acytokine-mediated immune disorder. The method includes administering atest compound to a test animal suffering from or at increased risk forthe immune disorder, wherein the test animal recombinantly expresses aCRF2-13 and measuring expression of the activity of the polypeptide inthe test animal. The activity of the polypeptide is also measured in acontrol animal that recombinantly expresses the polypeptide and is notat increased risk for the immune disorder. The expression of thepolypeptide in the test animal and the control animal is compared. Achange in the activity of the polypeptide in the test animal relative tothe control animal indicates the test compound is a modulator of latencyof the immune disorder. The cytokine-mediated immune disorder can be,e.g., an autoimmune disorder, a T-lymphocyte-associated disorder, acell-proliferation disorder, a cell differentiation disorder, or animmune deficiency order.

[0028] Also provided by the invention is a method for determining thepresence of or predisposition to a disease associated with alteredlevels of a CRF2-13 polypeptide in a subject (such as a human). Themethod includes measuring the amount of the polypeptide in a sample fromthe subject; and comparing the amount of the polypeptide to the amountof the polypeptide present in a control sample. An alteration in thelevel of the polypeptide in the subject sample as compared to the levelof the polypeptide in the control sample indicates the presence of orpredisposition to a disease in the subject.

[0029] Also provided by the invention is a method for determining thepresence of or predisposition to a disease associated with alteredlevels of a CRF2-13 nucleic acid molecule in a subject (such as ahuman). The method includes measuring the amount of the nucleic acid ina sample from the subject; and comparing the amount of the nucleic acidin the subject sample to the amount of the nucleic acid present in acontrol sample. An alteration in the level of the nucleic acid in step(a) as compared to the level of the nucleic acid in the control sampleindicates the presence of or predisposition to the disease in thesubject.

[0030] The invention also provides a method of treating or preventing apathological condition associated with a cytokine-mediated disorder byadministering to a subject (such as a human) an agent that increaseslevels of a polypeptide comprising the extracellular amino acid sequenceof a CRF2-13 polypeptide in an amount sufficient to alleviate or preventthe pathological condition in the subject. In some embodiments the agentis a polypeptide that includes the extracellular amino acid sequence ofa CRF2-13 polypeptide. For example, the polypeptide can be a fusionpolypeptide comprising the extracellular amino acid sequence of aCRF2-13 polypeptide fused to a non-CRF2-13 polypeptide). In otherembodiments, the agent is a nucleic acid encodes a polypeptide thatincludes the extracellular amino acid sequence of a CRF2-13 polypeptide.

[0031] Also provided by the invention is a method of treating orpreventing a pathological condition in a subject by administering to thesubject an antibody that binds specifically to a CRF2-13 polypeptide inan amount sufficient to alleviate or prevent the pathological condition.The subject can be, e.g., a human.

[0032] Also provided by the invention is a method of treating rheumatoidarthritis in a subject, the method comprising administering to thesubject an agent that modulates the amount of a CRF2-13 polypeptide inthe subject. The subject can be, e.g., a human. In some embodiments, theagent increases the amount of the CRF2-13 polypeptide in the subject.The agent can be, e.g., a CRF2-13 nucleic acid or polypeptide. In otherembodiments, the agent decreases the amount of the CRF2-13 polypeptidein the subject. The agent is an anti-CRF2-13 antibody.

[0033] Also within the invention is a method of treating multiplesclerosis in a subject by administering to the subject an agent thatmodulates the amount of a CRF2-13 polypeptide in the subject.

[0034] The invention additionally provides a method of modulatingvascular smooth muscle cell proliferation, the method comprisingcontacting a vascular smooth muscle cell with an agent that modulatesthe amount of CRF2-13 polypeptide in the cell.

[0035] In a further aspect, the invention includes a method of treatingor preventing inflammation in a subject, the method comprisingadministering to the subject an agent that modulates the amount of aCRF2-13 polypeptide in the subject.

[0036] Also provided by the invention are polymorphic CRF2-13 sequencescontaining one or more alterations in sequence relative to thenucleotide sequence disclosed in SEQ ID NO:3.

[0037] For example, the invention includes an isolated polynucleotidecomprising at least 10 contiguous nucleotides from nucleotide 30957 tonucleotide 30967 of SEQ ID NO:3, provided that position 30962 of thepolynucleotide is “A or “G”. In some embodiments, the isolatedpolynucleotide includes at least 15 or at least 20 contiguousnucleotides. In some embodiments, the polynucleotide is between about 10and about 100 nucleotides in length, e.g., between about 10 and about 90nucleotides in length, between about 10 and about 75 nucleotides inlength, between about 10 and about 50 bases in length, or between about10 and about 40 bases in length.

[0038] The invention also includes an isolated polynucleotide comprisingat least 10 contiguous nucleotides from nucleotide 30650 to nucleotide30660 of SEQ ID NO:3, provided that position 30655 of the polynucleotideis “A” or “G”.

[0039] In another aspect, the invention includes an isolatedpolynucleotide comprising at least 10 contiguous nucleotides fromnucleotide 28739 to nucleotide 28749 of SEQ ID NO:3, wherein position28744 of the polynucleotide is “A” or “G”.

[0040] In a further aspect, the invention includes an isolatedpolynucleotide comprising at least 10 contiguous nucleotides fromnucleotide 28442 to 28452 of SEQ ID NO:3, wherein position 28448 of thepolynucleotide is “C” or “T”.

[0041] In a still further aspect, the invention includes an isolatedpolynucleotide comprising at least 10 contiguous nucleotides fromnucleotide 9421 to 9431 of SEQ ID NO:3, wherein position 9426 of thepolynucleotide is “A” or “G”.

[0042] In yet another aspect, the invention includes an isolatedpolynucleotide comprising at least 10 contiguous nucleotides fromnucleotide 9157 to 9167 of SEQ ID NO:3, wherein position 9162 of thepolynucleotide is “A” or “G”.

[0043] In a further aspect, the invention includes an isolatedpolynucleotide comprising at least 10 contiguous nucleotides fromnucleotide 8806 to 8816 of SEQ ID NO:3, wherein position 8811 of thepolynucleotide is “C or “T”.

[0044] Unless otherwise defined, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In the case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

[0045] Other features and advantages of the invention will be apparentfrom the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0046]FIG. 1 is a phylogram showing polypeptide sequences related to aCRF2-13 polypeptide according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0047] The invention is based in part on the discovery of novel nucleicacid sequences encoding a polypeptide showing homology to CRF2polypeptides. Included in the invention is a 1563 nucleotide sequence(SEQ ID NO:1) shown in Table 1. Nucleotides 1-1560 of SEQ ID NO:1 encodea 520 amino acid CRF2-like polypeptide. The amino acid sequences of theencoded polypeptide is shown in Table 2 (SEQ ID NO:2). A nucleic acidhaving a portion of the 5′ untranslated region and a portion of thecoding sequence shown in Table 1 was identified in a human placentalcDNA library. TABLE 1 (SEQ ID NO:1)ATGGCGGGGCCCGAGCGCTGGGGCCCCCTGCTCCTGTGCCTGCTGCAGGCCGCTCCAGGGAGGCCCCGTCTGGCCCCTCCCCAGAATGTGACGCTGCTCTCCCAGAACTTCAGCGTGTACCTGACATGGCTCCCAGGGCTTGGCAACCCCCAGGATGTGACCTATTTTGTGGCCTATCAGAGCTCTCCCACCCGTAGACGGTGGCGCGAAGTGGAAGAGTGTGCGGGAACCAAGGAGCTGCTATGTTCTATGATGTGCCTGAAGAAACAGGACCTGTACAACAAGTTCAAGGGACGCGTGCGGACGGTTTCTCCCAGCTCCAAGTCCCCCTGGGTGGAGTCCGAATACCTGGATTACCTTTTTGAAGTGGAGCCGGCCCCACCTGTCCTGGTGCTCACCCAGACGGAGGAGATCCTGAGTGCCAATGCCACGTACCAGCTGCCCCCCTGCATGCCCCCACTGGATCTGAAGTATGAGGTGGCATTCTGGAAGGAGGGGGCCGGAAACAAGACCCTATTTCCAGTCACTCCCCATGGCCAGCCAGTCCAGATCACTCTCCAGCCAGCTGCCAGCGAACACCACTGCCTCAGTGCCAGAACCATCTACACGTTCAGTGTCCCGAAATACAGCAAGTTCTCTAAGCCCACCTGCTTCTTGCTGGAGGTCCCAGAAGCCAACTGGGCTTTCCTGGTGCTGCCATCGCTTCTGATACTGCTGTTAGTAATTGCCGCAGGGGGTGTGATCTGGAAGACCCTCATGGGGAACCCCTGGTTTCAGCGGGCAAAGATGCCACGGGCCCTGGACTTTTCTGGACACACACACCCTGTGGCAACCTTTCAGCCCAGCAGACCAGAGTCCGTGAATGACTTGTTCCTCTGTCCCCAAAAGGAACTGACCAGAGGGGTCAGGCCGACGCCTCGAGTCAGGGCCCCAGCCACCCAACAGACAAGATGGAAGAAGGACCTTGCAGAGGACGAAGAGGAGGAGGATGAGGAGGACACAGAAGATGGCGTCAGCTTCCAGCCCTACATTGAACCACCTTCTTTCCTGGGGCAAGAGCACCAGGCTCCAGGGCACTCGGAGGCTGGTGGGGTGGACTCAGGGAGGCCCAGGGCTCCTCTGGTCCCAAGCGAAGGCTCCTCTGCTTGGGATTCTTCAGACAGAAGCTGGGCCAGCACTGTGGACTCCTCCTGGGACAGGGCTGGGTCCTCTGGCTATTTGGCTGAGAAGGGGCCAGGCCAAGGGCCGGGTGGGGATGGGCACCAAGAATCTCTCCCACCACCTGAATTCTCCAAGGACTCGGGTTTCCTGGAAGAGCTCCCAGAAGATAACCTCTCCTCCTGGGCCACCTGGGGCACCTTACCACCGGAGCCGAATCTGGTCCCTGGGGGACCCCCAGTTTCTCTTCAGACACTGACCTTCTGCTGGGAAAGCAGCCCTGAGGAGGAAGAGGAGGCGAGGGAATCAGAAATTGAGGACAGCGATGCGGGCAGCTGGGGGGCTGAGAGCACCCAGAGGACCGAGGACAGGGGCCGGACATTGGGGCATTACATGGCCAGGTGA

[0048] TABLE 2 (SEQ ID NO:2)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSGRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

[0049] The nucleic acid of Table 1 encodes the 520 amino acid sequence(SEQ ID NO:2) shown in Table 2. Signal P and Psort results predict thatCRF2-13 protein contains a signal peptide, and is likely to be localizedto the plasma membrane with a certainty of 0.460. The most likelycleavage site for a CRF2-13 polypeptide is between amino acids 246 and247, at: AGG-VI.

[0050] The CRF2-13 amino acid sequence is related to other previouslydescribed interleukin-binding proteins. The relationship isschematically represented in FIG. 1. The CRF2-13 amino acid sequence ofSEQ ID NO:2 has 40 of 111 amino acid residues (36%) identical to, and 56of 111 (50%) amino acid residues similar to, the 231 amino acid residuehuman interleukin 22-binding protein CRF2-10 (gi|15212826|). Similarly,the CRF2-13 amino acid sequence has 32 of 86 amino acid residues (37%)identical to, and 43 of 86 (49%) amino acid residues similar to, the 130amino acid residue human interleukin 22-binding protein CRF2-10S(gi|15212830|). Moreover, the CRF2-13 amino acid sequence has 41 of 142amino acid residues (28%) identical to, and 58 of 142 (39%) amino acidresidues similar to, the 130 amino acid residue human interleukin22-binding protein CRF2-10L (gi|15212828|).

[0051] CRF2-13 polypeptide also shows homology to the amino acidsequences shown in the BLASTP data listed in Table 3A. Homologies arecalculated according to the method of Altschul and coworkers (NucleicAcids Res. 25:3389-3402, 1997).

[0052] In all BLAST alignments herein, the “E-value” or “Expect” valueis a numeric indication of the probability that the aligned sequencescould have achieved their similarity to the BLAST query sequence bychance alone, within the database that was searched. For example, theprobability that the subject (“Sbjct”) retrieved from the IIT BLASTanalysis, matched the Query IIT sequence purely by chance is the Evalue. The Expect value (E) is a parameter that describes the number ofhits one can “expect” to see just by chance when searching a database ofa particular size. It decreases exponentially with the Score (S) that isassigned to a match between two sequences. Essentially, the E valuedescribes the random background noise that exists for matches betweensequences. Blasting is performed against public nucleotide databasessuch as GenBank databases and the GeneSeq patent database. For example,BLASTX searching is performed against public protein databases, whichinclude GenBank databases, SwissProt, PDB and PIR.

[0053] The Expect value is used as a convenient way to create asignificance threshold for reporting results. The default value used forblasting is typically set to 0.0001. In BLAST 2.0, the Expect value isalso used instead of the P value (probability) to report thesignificance of matches. For example, an E value of one assigned to ahit can be interpreted as meaning that in a database of the current sizeone might expect to see one match with a similar score simply by chance.An E value of zero means that one would not expect to see any matcheswith a similar score simply by chance. See, e.g.,http://www.ncbi.nlm.nih.gov/Education/BLASTinfo/. TABLE 3A BLAST resultsfor NOV10 Gene Index/ Protein/ Length Identity Posit- IdentifierOrganism (aa) (%) ives (%) Expect gi|15212826|gb interleukin 231 40/11156/111 2e−08 |AAK85714.1| 22-binding (36%) (50%) (AY040566) proteinCRF2- 10 [Homo sapiens] gi|15212830|gb interleukin 130 32/86  43/86 2e−05 |AAK85716.1| 22-binding (37%) (49%) (AY040568) protein CRF2- 10S[Homo sapiens] gi|15212828|gb interleukin 263 41/142 58/142 3e−05|AAK85715.1| 22-binding (28%) (39%) (AY040567) protein CRF2- 10L [Homosapiens] gi|432|emb|CAA interferon 560 40/170 75/170 0.001 48484.1|receptor type (23%) (43%) (X68443) 1 [Bos taurus] gi|163188|gb|A alpha-560  0/170 75/170 0.001 AA02571.1| interferon (23%) (43%) (L06320)receptor [Bos taurus]

[0054] The homology of these sequences are graphically depicted in theClustalW analysis of Table 3B.

[0055] The presence of identifiable domains in the protein disclosedherein was determined by searches using algorithms such as PROSITE,Blocks, Pfam, ProDomain, Prints and then determining the ProDom orInterpro number by crossing the domain match (or numbers) using eitherthe Interpro website (http:www.ebi.ac.uk/interpro/) or the ProDomdatabase(http://www.biochem.ucl.ac.uk/bsm/dbbrowser/jj/prodomsrchjj.html).Tables 3C-3E list the domain descriptions from DOMAIN analysis resultsof CRF2-13 polypeptide using Pfam (Table 3C) and ProDomain (Tables 3Dand 3E). This indicates that the CRF2-13 protein sequence has propertiessimilar to those of other proteins known to contain these domains. TABLE3C Domain Analysis of CRF2-13 Protein gnl|Pfam|pfam011O8 Tissue_fac,Tissue factor (SEQ ID NO: XX) CD- Length = 293 residues,61.1% alignedScore = 37.0 bits (84), Expect = 0.003 Query: 9PLLL--CLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRR 66 |||   | | |          |+|  | ||   | | |    | +  | |  | | Sbjct: 19TLLLGWLLAQVAGAAGTTEKAYNLTWKSTNFKTILEWEP---KPINHVYTV--QISTRSG 73 Query:67 RWREVEECAGTKELLCSMMCLKKQDLYNKFKGRV--------RTVSPSSKSPWVES-EYL 117 |+   +|  | +  | +     +|+   +  ||        +|     + |+  | |+ Sbjct: 74NWK--NKCFYTTDTECDLTDEIVKDVTQTYLARVLSYPARNDQTTGSGEEPPFTNSPEFT 131 Query:118 DYL-----------FEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWK-E 165 ||           ||       + +     ++  | |+     +   || | + +|| Sbjct: 132PYLDTNLGQPTIQSFEQVGTKLNVTVQDARTLVRRNGTFLSLRDVFGKDLNYTLYYWKAS 191 Query:166 GAGNKT 171   | || Sbjct: 192 STGKKT 197

[0056] TABLE 3D Domain Analysis of CRF2-13 Protein PD338678(Q9UHF4_HUMAN 36-246)COAGULATION FACTOR III PALMITATE TISSUE LIPOPROTEINSIGNAL GLYCOPROTEIN TRANSMEMBRANE PRECURSOR (SEQ ID NO: XX)Score = 101(43.3 bits), Expect = 0.003 Identities = 33/118 (27%) , Positives= 50/118 (41%) Query: 24LAPPQNVTLLSQNFSVYLTWLPGLG-NPQDVTYFVAYQSSPTRRRWREVEECAGTKELLC 82|  | |+| || |    | | |  |     ||| | |     +++|    ||       | Sbjct: 37LPKPANITFLSINMKNVLQWTPPEGLQGVKVTYTVQYFIY-GQKKWLNKSECRNINRTYC 95 Query:83 SMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILS 140 +   +  |  +++  +|+ +  +  | | ||       | +  || + ||  |+ +| Sbjct: 96DLSA-ETSDYEHQYYAKVKAIWGTKCSKWAESGRFYPFLETQIGPPEVALTTDEKSIS 152

[0057] TABLE 3E Domain Analysis of CRF2-13 Protein PD008555 (INR1_MOUSE19-216)RECEPTOR TRANSMEMBRANE GLYCOPROTEIN PRECURSOR CHAINSIGNALINTERFERON-ALPHA/BETA IFN-ALPHA-REC (SEQ ID NO: XX)Score = 98(42.1 bits), Expect = 0.007 Identities = 46/207 (22%), Positives= 88/207 (42%) Query: 14LLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEE 73+| +| |   | ||+|+ +   + +  | |     +   ||+   |++     +| +| | Sbjct: 19VLPSAAGGENLKPPENIDVYIIDDNYTLKWSSHGESMGSVTFSAEYRTK-DEAKWLKVPE 77 Query:74 CAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLT 33|  |    |    |   ++| | + |||    +| | | | +     +    +|| + | Sbjct: 78CQHTTTTKCEFSLLDT-NVYIKTQFRVRAEEGNSTSSWNEVDPFIPFYTAHMSPPEVRLE 36 Query:134 QTEEILSANATYQLPP-------CMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITL 86  ++ +  + +   ||        +      | +  |++ + +|     | + + +   | Sbjct: 137AEDKAILVHIS---PPGQDGNMWALEKPSFSYTIRIWQKSSSDKKTINSTYYVEKIP-EL 192 Query;187 QPAASEHHCLSARTIYTFSVPKYSKFS 213  |  +  +||  + |+  |+ |+| +| Sbjct:193 LPETT--YCLEVKAIHP-SLKKHSNYS 216

[0058] Growth factors such are proteins that bind to receptors on thecell surface, with the primary result of activating cellularproliferation and/or differentiation. Cytokines (e.g., lymphokines;interleukin and interferon) are a unique family of growth factors. Anumber of receptors for lymphokines, hematopoeitic growth factors andgrowth hormone-related molecules share common domains, and can bedivided into families. The cytokine receptor class 2 family includesinterleukin-10 receptor; interferon-gamma receptor;interferon-alpha/beta receptor; and tissue factor (Konigsberg et al.,Nature 380:41-46, 1996). The presence of regions of CRF2-13 polypeptiderelated to domains found on tissue factor and coagulation factor IIIpalmitate tissue lipoprotein signal glycoprotein transmembrane precursorare consistent with the localization of CRF2-13 polypeptide to theplasma membrane and the assignment of CRF2-13 polypeptide to thecytokine receptor superfamily. The presence of a region of CRF2-13polypeptide related to interferon 1 receptor transmembrane glycoproteinprecursor signal chain interferon alphalbeta IFN-alpha receptorreinforces this assignment.

[0059] The nucleotide sequence shown in Table 1 was identified as partof the genomic DNA sequence shown in Table 4: TABLE 4 1 GAAAGAGAGAGAAAAAAGAA GGAAGGAAGG AAGGAAGGAA GGAAGGAAGG (SEQ ID NO:3) 51 AAGGAAAGAAAGAAAGAAAG AAAGAAAGAA AGAAAGAAAG AAAGAAAGAA 101 AGAGAGAGAA AGGAAGGAAGGAAGGAGAAA AGAAAGTCAA CAGTCAACAT 151 TTCAGAGATC CCAAGATACC AACACTGACCGTGCCTGCTG CTCTTCCATC 201 CTCCTCCACC CTGCGCCTTT GAGGTGGAAT TGCGTCCTCTGTGAGCAGGG 251 CTTTGTTAAG AGATCCTAAT TAAGGCCAGG CACAGTGGCT CATGCCTGTA301 ATCCCAGCAC TTTGGGAGGC TGAGGTCACC TGAGGTCAGG AGTTCAAGAC 351CAGCCTGCCC AACATGGTGA AACCCCATCT CTACAAAAAT TAGCTGAGCA 401 TGATGGCAGGTGCCTGTAAT CCCAACTACT TGGGAGGCTG AAGTGAGAAA 451 ATAGCTTGAA CCCAGGAGGCGGGGTTGCAG TGAGCCAAGA TCACACTATT 501 GCATTCCAGC CTGGGCGACA GAGCTTTTGTCTAAAAAAAA AAAAAGAAAA 551 AAAATCCTGA TTAAGCAGAA GCCTTGATGC TAGTCCCAGAAGCATCCTGA 601 AATTTCCAAA AGAAATTTCC CCCGCGGTTA AACTCAGAGC AACTTTTGGA651 CCCACCAAGC TCTGTGAAAA TCATTTTCTC TTCCAAAAAC TGATGGGACC 701AAAGCTGATC CCAGTTTCAA ATAATTATCA AAAAATTGGA AACGAAATAT 751 GATCAGAAAAGAAGAAAGTT GAAAAAGAAA ATCCTTATCA CCCAAAGACA 801 ACAACCATTA ATATTTTGGTAATTATTATT ACAAATATCT TTCTATGCAT 851 ACAGACAGAC TCACACACAC ACACACACACACACACACAC ACTTTTTTTT 901 TTTTTTTTGA AACTGAGTTT CACTCTGTCG CCCAGGCTGGAGTGCAGTGG 951 CGCGATCTCG GCTCACTGCA ACCTCCGCCT CCTGGGTTCA AGCGATTCTC1001 CTGCCTCAGC CTCCCTGATA GCTGGGATTA CAGGTGAATG CCACCACGCC 1051CGGCTGATTT TCTGTATTTT TAGTAGAGAC GGGGTTTCAC CATGTTGGCC 1101 AGGCTTGTCTCCAACTCCTG ACCTCAGGCG ATCCACCCGC CTCACCCTCC 1151 CAAAGTGCTG GGATTACAGGCGTGAGCCAC CGCGCCCGGC TACACACACA 1201 CTTTTTTAAT GGGCCTATGT TTTAGCACTCGCTTTTCTGT TTCTCAGTGT 1251 GTTGCAAACA CCTCGGTGTC GATACACACC ATTCGGCAACGTCCTCCTAA 1301 AGGGCCGCAT AATATTGCGC GTCGTGGCGT GTGCCTTACT GGGAAGCTAC1351 TGCTGTCCAG GTGAACACCA CAGCCTTCGG GGTCAGAAAG ACAGCTTTCC 1401CCAGAACAAG CACCTGAAGC TCTGGGGCCT GCCGCTCCCC GGGTAGAGAA 1451 GTACGTGGAGAAGGGCAGCA CGGATCCGCC GGGATCCCCG GGGGCATTAA 1501 AGGGAATCGC GTGTGTAAGGCGCGGAGCTC AGCATCCGGC TCAGAAACGC 1551 GCTCGGATCC CGCCAATGGC ATTGAGGCCGCGTAGCCAAA CCGGCCTTGA 1601 ACTCTCCCTA ATCCTGCCAA AATGGCCCGT CCTGGAGCACTGGACTGGCC 1651 GTGGGTTATT GATCATCAGC CGGTTTCTTC CCCTCCCCTG CCCTTCCCCC1701 GTGCACGGAT TTACTGATTT TTTTTTCCGG GAATTGAGTA AAACAAAACT 1751AAGTGCAGAT GAAGCAGAGG TACGGGCGAG TTTCGAGCGC GGGGACCGGC 1801 GCGCTCCCCCCCCCCTCCCC CCGCGGCGGG GCTGTCCCCA GGGACCTTCT 1851 CAGTGAATCC TAGGCGGCAGGGACGGGCCC GCGGCTCTGC GGGCCATTGG 1901 CTGCCGACTG CGTCACCTGC CCGCGGTGGGCTAGGAGACG GGAGGCGGGA 1951 GGCGGGAGGC GGGGACCTGG GTCCGGGCGG GGACGCCGCGGCAGGAAGGC 2001 CATGGCGGGG CCCGAGCGCT GGGGCCCCCT GCTCCTGTGC CTGCTGCAGG2051 CCGCTCCAGG TAAGGGCGCG GGGCCGCGGG AGGGAGGGGG AAGAGGGCTC 2101CCCGGGCCGG GCCGCGCCTA CCCTCGGACC CAGAGCTCCT GGGACAGGCA 2151 CGGGGTCCGCAGCCACCCGA GCCGGGTGCG AATCGGCCCT GCCTACGCGC 2201 CCCCAGTTTG CTTCTTCCCAGGACTGAACA GAACCGGGTC TTTGATATTC 2251 CTCTCCCGCA GGAAACGAAT CCAGTTTCCTAATGCTTCCA GCTTCAGGAG 2301 AACTGGAGAA AAAAGACAGC GGCAGTTTGA TACTGCATATTTTTTAATAA 2351 AGTGCTTTTT AATGTTTCCT AAAGAAAGCA CTGATCCCTG CGTGAAAACC2401 ACACTTGACC CTAAAGTGTG GACAGCAGGG AAAGTGGGAC CGATTGATGT 2451CCCTTCCCGT TCCTGCCAGG CCTCTGGTGG GACGGAGCTC TGGTCGCCTG 2501 TGCCCTGCTTTCTAACAAGA CGGCTTTCTT TTGGTGGTGG TTGTTGTTTT 2551 GTTGTTGTTT TGTTGTTGTTGTTGTTGTTG TTGTTTTCCC ACCTCTACTG 2601 ATGAGTAAGG TGTCAGGTAC AAAATTCCTCGCCGTAGGAC CCAACCACCA 2651 AACCTCACCG CCCACGACTC CAACCGAAGC AGGGAAGAGAAGGTCCAGAA 2701 ATCGCCCCCA GGATATTTTC CTAGTCTTGG ACTCACAGTT TAAAGAGCTG2751 TAAAGGTCCC TGGGCATAAT CCAATCATCA TAAAAGCCTA TATTTATTCA 2801GCAACTTCTT TGTGCCAGGC ACCGCATTAT TCTGGAAGCC TCACGACCCA 2851 GCCATCCTAGGAGGTAGATA TTATTTTTAC TTTTCCGATG GGAAAACTGA 2901 GGCTCAGAGC AATTCAGGGAATTCCTCAAG AAGGACGGCA GAGGTGAGGC 2951 ACACAGAAGA GAGAAGAGGG GCTAAAGCAAGCCTGGCTAG CTTTTGCCTC 3001 CAGGGTAGGC ACGTGGGACA GGCTGTCCAT CCACTGGGTCACTAGGCCAG 3051 CCAGGGATGC TCCAGCCCCC AGTGCCCACA GCAGCGTTCT CTGTGGCTGA3101 TGAGGGACCG TGTACCTGTG TGTGGAGGGA GGGTGGGGTC TTCTGTTCCC 3151CTTTCACTGT CAAGCCCAGA CCTTCTTGTA CTTTCACCTG ATAAGTATTT 3201 AATATACACAACACTAACTA TGGTGTGATG ATTTAGGAGT AAGTACAGCC 3251 AGATCTAAGT TCAAATACTGGCTCCCACAC AAACTGACTG TGTAGCCTCA 3301 GGCAAGTTAG TTAGCATCTG TCTCTGAGCCTAGCGCCCTT TCCATGGAAG 3351 CAGAATGAAT GACACCTACC CCATAGGGTG GTCTGTCCCAAGGGTGATTG 3401 AGGTTTTACA TGTAAAGAGC CAAACTAGTG CCTGGCATCC TTTGAAGGCT3451 TCATAGAGGA AAGTTGCTCT AGCTGCTGTT TTTCTCATGT GACCTAGCTC 3501GAATCTGGGG ACTGTCCTGC CCATAGGATA CCTTACAAGT GGCTTGCAGA 3551 CAGCCTGGTCTCCTGCTGGT CACCCGTTAG GAAGTCCAGA AGCTGGGAGT 3601 AGTAATAGCA CTAGCCTCGTGGTGATACAG TCCCAGCTAG AGGACACAGG 3651 ATGAGGTGGA AGCAGGCACC CACTTTTGGGTCTAAAAGGT GATGGGTAGG 3701 CAGCCGAGGC TGGGGACAGC CATCCACAGA ACTGGACCCTCCCTCCCTGA 3751 TGCCATTTTG CAACCCGTAT GGATTTCCAT CATGGCACAT GGGACACTTC3801 AGGACCCTGA ATTCTCCATG GGACCATGAG CTCCTATAGG GCAGGAATGA 3851AGTTGTGTTC TTCTTTGAAA CCCCTGGCAC ACCGTGGTCA ACAGATCTTG 3901 TTTGACTCGTAGTGGTCAAT AGATGGAATA GTTGGAATCA TAAAGCTCAA 3951 TAGACCCCAT GAGAACCTAGAAGACAAAGT ACAGTCAAGA GCTCGGACTT 4001 TGGAGTTGGC TAGGCCTGGA CTGAATCTGATTCTACAACT TAATAGCTGA 4051 GAGGGCCTTG GTTTTCCCAT CTGTAAAGAT TATAATTATTATAATGAATA 4101 CCTACCTCCT AGGGATGTAA TGAGGATTAA AAGAGAAAGT GCAGGTAAAC4151 TGTTTAACAC AGAACCTGGC TCATAGAACA CAATACACAT TAGCTGCTAT 4201TATTATTATT ATTATTTTAT TTATTTATTT TGAGACAGAG TCTCACTCTG 4251 TCACCCAGGCTGGAGTGCAG TGGCGCAATC TCGGCTCACT GCAACCTCCA 4301 CCTATCGGGT TCAAGCAATTCTCGTGTCTC AGCCTCCCAA GTAGCTGAGA 4351 TGACAGGCGT GTGCCACCAT GCCCAACTAATTTTTGTATT TTTAGAAGAG 4401 ACGTGGTTTC ACCATGTTGG CCAGGCTGGT CTCAAACTCCTGACCTCAGG 4451 TGATTTGCCT ACCTCTGCCT CCCAAAATGC TGGGATCACA GGGGTGAGTT4501 ACCATGCCCG GCCTTAGCTG CTATTATTAT CATCATCGTT ATCATCATCA 4551TCATCACCTC GTAGATATGT CAAGGAAGAT TCCCTGGAGG AAGTGACATT 4601 TGAATCAAGTATTTCAAAGA CTAGATGGTG AATACCAGGC AGTCAAAGAC 4651 ACCTGGGTTT AAAAACATCCAGAAGAATGC AGTGGCTTGG CAACATCGAG 4701 CAGGAAGATT GCCTGATGAG CCTGTAGGGTAGCTGTTGGG GAGAGAGCAG 4751 CAAGACGGCC TGGCCAGGCC AGGCCAGGCC ACGTCAGGCAGGGCCTCACA 4801 AACCTCAATA ACAAATGTGG ACTTTATTCT GAGGCCAAGG AAAGGGCATG4851 AAACTGGGGA GTGGTGTAAT CAGATGCGTA TTTCAGAAGA TGAAGATTAA 4901CAGTGAGAAG GAAAATGTGC CACAGAGGGG AATAGAGGTC AGTTAAAGGG 4951 AGTCAGGGAAAGTGTCCTCG AGACAGTGAC ATCAAAGGAA TGTGAAAACA 5001 GCAAAGGAGT GAGCCAGGTGGATATCCAGG GGCAGAACTG TTAAGGCAGA 5051 GGGAACAGCA TGAGGGAACA GCGTGTGCAAAGGCCTGGAG TTGGGAGTGT 5101 GGCTGGGGTG CTCCAGGAAG GGCAAAAAGT CCTGTGTGGATGGAGATATG 5151 GGAGCAAGGG AGGAGTGGTG GGTCAGATTG GGTAGGGCCT TGGTGGTGAT5201 TGTAAAGACT TTGGAGTTTA GACCAGGCAC AGTGGCTCAG GCCTGTAATC 5251CCAGCACTTT GAGAGGCCAA GGTGGGCGGA TCACCTGAGG TCAGGAGTTC 5301 GAGACCAGCCTGTAATCCCA GCTACTCTGG AGGCTGAGGC AGGAGAATCG 5351 CTTGAACCCG GAAGGTGGAGGTTGCAGTGA GCTGAGATTG TGCCACTGTA 5401 CTCCAGCCTG GGTGGCAGCA TAAGACTCTGCCTCAAAATA AAATAAAAAT 5451 AATAAAGACT TTTGAGTTTC CCTGGAGTGA GAGGAAAGCCTTAGAGGGCT 5501 TTAGCAGAAG ATGAACATGA TCTGATTTTC ATTTTTAATC CTTCCCTGCT5551 AATGTGGAGA ATGGACTGAA GGCAAGGTGT TTTGTATATT TGTCTGTTTC 5601GTAGAGACAG GGTCTTGCTC TGTTGGCCAG ACTGAAGTGC AGTGGCACAA 5651 TCACGGCAGCCTTGAACTCC TGGGCTCAGG CGAAACTCCC ACCTCAGCCT 5701 CCTTACTCTC ACCATTGTGCCCTGCTAATT TTTTAAAAAA TTTATTTTGT 5751 AGAGATGTGG TCTCACTATG TTGCCTAGGCAAGTCTTAAA TTCCTGGTCT 5801 CAAATGATTC TCCTGCCTCG ATGTCCCAAA GTGCTGGGATTACAGGTGTC 5851 AGCTGCCATG CCCGACCTGT ATTTTTTTTT TTAATGGGGA AAAAGCCTTT5901 TAATAGTATG AGGTGTTTTC TGGTGTTTCT ACCATAAAGC TCTTCTGTAA 5951ATCAAAATGA GAATGTAATT ATTGATAGAG CAATGACCTT AGACTACAGT 6001 GCAGACTTTTCATCTTACAT TTGGGCTCAT GAATTTTAGT ATAACTGATT 6051 ATGACAGTGT TTTTTACATAGTTATGATCT AGAGCAGAAC TGAAAACAAA 6101 ATAACACATA CTCTACATCA ATATATTCGTTCAGTAATAT CTGGGCTTGG 6151 ATGAACCTGC AGAAGTAGGT AAAGCTGTCA GATATTTTCTTAAACCAACA 6201 GAAAAGAAAT GTATATGACA GATGTTGTGT TTACTTACTT ATTTATTTAT6251 TTATTTATTT ATTTGAGATG GAGTCTCACT GTGTCACCAG GCTGGAGTAC 6301AGTGGTGTGA TCTCTGCTCA CTGCAACCTC CACCTCCCGG ATTCAAGCGA 6351 TTCTCCTGCCTCAGCCTCCT GAGTAGCTGG GATTACAGGC GTGCACCACC 6401 ACGCCTGGCT AATTTTTGTGTTTTTAGTAG AGACAGGGTT TCACCATGTT 6451 GGTCAGGCTG GTCTCGAACT CCTGACCTCGGGATCTGCCC ACATCAGCCT 6501 CCCAAAGTAC TGGGATTACA GGCATGAACC ACCACGCCCAGCCTGTATTT 6551 ATTTTTTTAC CACTATGGAG TCCAATATGA AATTCTCACA ACTATGCATA6601 TACATTATTA ACATGTAAGC ACACCTAGGT ATAAATATGC ACATAGTCCA 6651TTAATTACAT CAGGGGAATT AAAAACATAC TTTCAAGTTA AAATGAATTT 6701 TCAGGAAAAAAACTGCATTC ACAAATCTGA AATGTGAATA CAAAAATGAA 6751 ATTGTGAAAT AAATAATGAATATAGGTGTC ACCTAAACTT CCATAGTAAC 6801 ATGCCTCCAA ATGTGGATTT AGTGATCATCCACCTTGGGA CAAGGGCTTT 6851 TGAGAGCCTC CAGCTAAATT AGGGTTCCAG TAGCAGAGTGGCTGGCAAGC 6901 CTGCCCTAAT GAATAATGCC AGCGAGCTGG GCGTGGGTAC TTACAGTGTG6951 CCCTTCATGG AATACTTTTT TTTTTTTTTT TGGAATGGAG TCTCGCCCTG 7001TTGCCCAGGC TGGAATGCAG TGGCACAATC TCAGCTCACT GCAACCTCGT 7051 CCTCCTGGGTTCAAGCAATT CTCGTGCCTC AGCCTCCCAG GTAGCTGAGA 7101 CTACAGCCCT GTGCCATCATGTTCTGCTAA TTTTTGCATT TTTAGTAGAG 7151 ACGAGGTTTC ACCAAGTTGG CCAAGACTGGTCTTGAATTC CTGACCTCAG 7201 GTGATCTGCC CACCTTGACC TCCCAAAGTG CTGGGATTACAGGCTTGAGC 7251 CACTGCGCCC GGCCCATGAA ATACTTCTTA CCTGGCGGAC AGCCTAATAG7301 CCTAGCTGTC TAACCCATGG CTGGGGGTCC TTCACACTTG TTTATACTGG 7351CAGACGTCCC TGTGACTCTT GTCTGATCCA TGTCCAAGTT TATGCCTGTC 7401 TGACCATTGCTCTGGCGCTG GGAGCCAGAC TGTGTTCCCA GCAACCCAGG 7451 GAAAACCAGG CCTGGGCTGGGCCTGGGTTC CTGAGATGGA AGGTGCAAAT 7501 TCAGTACACC ACCTCAATGC AAAACAAGTTCAAAGGCTTA TTACTTACAG 7551 ATCCTGAGCA GGGAAGGTGC AATGAGTAGG GAGGGTCATCCTCCATCCTG 7601 GGCTACATGA AGCGGGAATG AAGAGTCAGG CAAAAAGAAA GTGAGAGCTT7651 GTGGCAATGA GAAGTATATT ATGTAAGGGA CTAGGGTGTG GGTCAGGTTA 7701AGTTTGAGGG CAAATGCTTG AATGATCCCT TTAAAGGAAT GGGTGGGAAG 7751 TGGGGAGCCCAGTTTGCCGG GAGGGAGAGA TGCCTCGAAG TTCTTATCTC 7801 TGGCCACTGG CTTGGGCCATCTGAGTGTGG CATCTACTTC TAATGCCTAG 7851 GCAGCAACCT TTGCTGTGTC ATCTCCCTTACACAAGGTTG GAAGCAGGGA 7901 GACCGGTCAG GAAGCCTTTG GTGTAACCCA TGTTATTGTAATATTCATTC 7951 ATTTACTCAA CAGATGTTTA TTGTGCACCT ACTATGTGCT GAGGCCATGG8001 CAGGCAGGCT CTGGGGATGT GGCTGAGAAC AGGACAGAGC CCCTGGTCCT 8051TGATATCCTC AAGGATGCTC CCTCCTGGAG GCCATTAGGT TCCTGTTCCA 8101 TGGTGTTCTGCTGGAACCCT CCGGTCCCAG AGTGTGCAGG AGCCTCCCCT 8151 CCTGGCAAAG GGTCTTCTCTCATGGCACAA GGGCTGCAGT ACAGCCAGTC 8201 AGTGGCTCCT GGTTCCTCAA ACTCAGTGAGCACTTGCCTG CCCTTCGTGC 8251 TGCCCCTCAG CTTGGGATGG CCTGAGTCAA GACCAGCCAGGAGCTCCAGG 8301 CTTCATGACC CCTTTCTTTC CCCCAGGGAG GCCCCGTCTG GCCCCTCCCC8351 AGAATGTGAC GCTGCTCTCC CAGAACTTCA GCGTGTACCT GACATGGCTC 8401CCAGGGCTTG GCAACCCCCA GGATGTGACC TATTTTGTGG CCTATCAGAG 8451 GTAGAGGAGACTCTCTCGGC TGGTGGATGG GAAGACTGAG GGGGTGGGTG 8501 GGGGCTTGGA GGGGCTTCTCTGGGACAGCT GCACCCAGTG TGGGCAGCAC 8551 TGGCTAGCTC TCTGGGCCCT ACGGGAGATGGCATGTGGCC GGCATTTGGA 8601 GAGGGGCTTT TGATAAAGGT CTGGAGGTGG GGAAGATGTTGAATGAAGAG 8651 CAGTGTACAG GTGACCAGTC TGCCGGGGCG GGGGTAAGTC TTTGAGGAAA8701 GTTGGTGTGG GGCATGGATG TAGCTGTGGG GGCCAGAGGA TGAAATTCTC 8751AAGTGGCTGG ATGAGGTGCT TGGAGCTGTC CCAGCTGATC AGTGAGGCAA 8801 CTAGGTACACGGCAGAGGAG CTGTTACCTG GGCAATTAGG CATCCCTCAA 8851 TGATCACACT TTTTTTCTCTTTTTTTTTTT TTTTTGAGAC AGAGTCTTGG 8901 TCTGTCACCC AAGCTGGAGT GCAGTGGCTTGATCTCGGCT CACTGCAACC 8951 TCCACCTCCT GGGTTCAAGT GATTCTCCTG CCTCAGCCTCCAGAGTAGCT 9001 GGGATTACAG GCATATGCCA CCACATCTGG CTAATTTTTG TATTTTTAAT9051 ACAGACGAGG TTTCTCCATG TTGCCCACGC TGGTCTCGAA CTCCTGAGCT 9101CAGGTGATCC ACCCACCTCA GCCTCCCAAA GTGTTGGGAT TACAGGCGTA 9151 AGCCACCGCGCTTGGCCAAA TGGTCACACT TTTCCCGATG GGATCATTCT 9201 CAATTTGGAA GCCCAGGCAGCCACAGCGAA TCCAGAGAAA TCTGACAATG 9251 GAAGCAGATC CACCATCTTC GAACATAGATGGGAATCGTT CAGAGTTCTT 9301 TAGCAGGACA GTGAGATGAT AGAAGCAGAA GCTCGGGAGGATTCACCTGG 9351 AGTTGGTGAG GAGGGGAAAG CAGGAAGAGG AGGGGACCCA CCGTGTCCTC9401 AGGACCCGTC CTGTGCCAGG CCAAGTGCTA AGGGCCCTAC GTGAATATTT 9451CACTTCCTTC TCCCAATGTG ACCAGGCAGG CTCTGTGTTT TCCCCATTCT 9501 AGAGGTGAGGGGGATTGAGC ACTGTGTCAA CACATGTAAT GAACTTAATC 9551 TCACAGCAGC TCTCTGAGGACAAGTTCAGT ACGCCTCTTT ACAGAGGAGG 9601 AGACTGAAGC ACCAAGGGTG CATGTTGCTCAAAGTCACAC AGCTGGGCGT 9651 AGTATGGCTG GAATAAATTT ATTAAGGAGT TGAAAGTCTATCCTCTAGGA 9701 CCAAGCATGG TGGCTTACAT CTGTAATCCC AGCACTTTGG GAGGCCGAGG9751 TGGGTGGGGA GATTGCTTGA GTCCAAGAGT TCCACACCAT CCTGGGTAAC 9801ATGGTGAAAC CCTGTCTCTA CAAAAAAAAA AAATACAAAA AATTAGTGAA 9851 GTGTAGTAGCATGTGCCTGT GTTCCCAGCT ACTTGGGAGG CTGAGGTGGG 9901 AAGGATCACT TGAGCCCAGGAGATGGAGGT TGCAGTAACA AAGATCACAC 9951 CACTGCACTC CAACATAACA ACAGAGCAAGATCAAAAGGG TTTTTAGCTC 10001 CCACTGAACG CCNCGTCATA NCCTTAGGTN NNNNNNNNNNNNNNNNNNNN 10051 NNNNNNNNNN NNNNNMNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN10101 NNNNNNNNNN NNNNNNNNNN NNNNNNNNNG AACAACAGAG CAAGATCCTA 10151AAAAGAAAGA AAGTCTATCC TCTGAACTTC TATGATATTT TTCATGTCTT 10201 TTATACATTAGAATGGTGAT ATTCTAATTA TATAATTTTT TTCATTTGTT 10251 AGTTGGAATT ATTTTATAAAGAGATGTATC CTCTCATCTG GTATTTGATA 10301 TCCAGTCATA CTATTCAAAT AGGCAAGAGAGGATAAATGC TTAATTTTTT 10351 TCCTTTATCA ATTTTCAAGA TAATGAATTG GTTCCTTATCATCTCCCAAA 10401 GGTGATTGCT AGTTTATTAT TATCATTATG AACTCAGGCA TTTAAACACA10451 TTTGGTGGTT TCAGTCTATT GCGACGTACT CTGCTCATTG AAGCTTGAAT 10501TGCCTCATCT CTGTCCAGTG GGAGTCTCAT CAAGTTTGCT CCTGAGTCCT 10551 TTTAACTTGACCCTAGTGGT CAAGTTAAAT CTTTCCAGAT TTAACAGATA 10601 CCTTTCCAGC TGTCCATTACGACAAGATGT TCCAGGTCCC TCTGGTACAA 10651 TTCCTGACCT AAAACCTGCA GTCAGCCATTTCTCCATTTA GTAAGAAATG 10701 GTTATAAAGA CTATAATCTG CATGCTAGCT ATGCTGATCACTACTTAGCT 10751 ATTGCTTTTG GTGTTTTCAG TGAACAGAGT GATGTGTGTA TACCACATAG10801 ACACACACAT GTACATACTT TTTTTTTTTA GACAGAGCTT CACTCTGTCA 10851CCCAGGCCAG AGTGCAGTGG CATGATCTCG GCTCACTGCA ACCTCCACCT 10901 CCTGGGTTCAAGAGATTATC CTGCCTCAGC CTACTAAGTA GTTGGGATTA 10951 CAGGCGCCCA CCACCATACCCGGCTAATTT TTGTATTTTT AGTAGAGACG 11001 GGGTTTCACC ATGTTGGCCA GGCTGGTGTCGAACTCCTGA CCTCAAGTGA 11051 TCTGCCCCCC TCGGCCTCCC AAAATGCTGG GATTACAGGCATGAGCCATC 11101 GCACCCAGCC TACATGTACA TAATTTTTAA GATAAAATGC CTAATGAGTT11151 ATACGGGTGC TTCCCATCTA AATTTAGTTC CTTAGGATTT TTACCTGACT 11201TCTATGGTAC ATCTATATTT TCTTTCTTTC ACACTGAGAA TCCTGTTTCT 11251 CAAGGACAGGGGACATGATA GAACTAGAAT GACCCATAAT TACTCATTTT 11301 CTTTATCCCA AAACATACATACTTGCCTCT TAATAGTTTC TTGCTCTTTT 11351 CGCCCAAAGG GTTTGTGATG GTCAATATTAGGTGTCAACT TAATTGGGTT 11401 GAAGGATGCC TAGATGGCTG TTAAAGTTTT GTTTCTGGGGGTGTCTGTGA 11451 GGGTGTTGCC AGAGGAGACT GACATTTGAG TCAGTGGACT GGGAATGGAA11501 GACTCGTCCT CACTCAGTGT GGGTGGGCAC AACCCAACTG GCTGCCAGGC 11551TGGCTGGAAA GCAGGTGGCA GATGGTGGGA TAGCTTCACT TGCTGGGTCT 11601 TCCAGCTTCCTTCTTTCTCC CGTGCGGGAT GCTTCCTTCT GCTCCTCCTG 11651 CCCTTGAACA TCACACTCCGGGTTTTTTGG CCTTTAGACT CTTGGACTTA 11701 AGTTAGTGGT TTGCTGGGGG CTCTCGGATCTTTGGTCACA GACTGAAGGC 11751 TGCACTTTCA GCTTCCCTGG TTTTGAGGGT TTCAGATTCGGACTGAGTCA 11801 CTATGGCTTC TTTCTTTCCC ACCTTGCTGA CGGCCTATCG TGGGACTTCG11851 CCTTGTGATC GTGTGAGCCA ATTCTCCTTA ATAAACTCCC TTTCATATAT 11901ACGTATAACC TATTAGTTCT GTTCCTCTGG AGAACCCTGA CTAATAAAGG 11951 GTTGTTGCTTTTTCTTTAAA ATCTAGTAAT TTTATTTGAC TGTGTGTTGG 12001 TATTGCTCAT TCATTCTGAGTTGATATTTT TAGGCACTCA ATATTCTCAC 12051 TTAATACATG GTTCCAAGGC ATTTTTATTTTAGGAAGGTT TTCTTAAATT 12101 ATAGTTTTAG TATTTGTTCT ATTCTCTTGT TTTGATTTTCTTCTTTAGGG 12151 ACTCATATCA CTTGTATGTT GGATCTTCTT TTTCTGTGTT CAGTATTTGT12201 CTTTTGGGCA CAGAGACTCA CACCTATAAT TCCAAGACTT TGTGAGGCAT 12251AGGTAGGAGG ATCGCTTGAG CCCAGGAGTT TGAGACCAGC CTGGGCAACA 12301 TGGTGAGGCCCTGTCTCAAA TTAAAGAAAA AGGAGAGAAT ACTTGTCTTT 12351 TTCTTTCAAA TGCCTTTTATCTGTCTGTCT ATCTACTATT CTGCTCTCTA 12401 AATGAAATAG GTTTCACTCT TGAGTTTTTAAAAAACTGTG TGCTTCCATG 12451 TGTGAGATTA TTCAACATCT TATTTGTAAT CTTTCTCTTGGTTACATTTA 12501 TTTTTCCTGA AAACTCTAGT CTGCTTTTAG CTGACATGTT TGTAGCTAAG12551 AGCGCACATT TCTTATCATA GCTTGCCGTG CTGAATTAAT TCCAATTTTC 12601TTTTAAAACC AACATTATTG AGTTAAAATG TATATAGAAT AAACTGTTCC 12651 CATTTTAAAGTATACAATTT GATGAGTTTT GACAAAAGTG GGCACCCACG 12701 TACCCACCAC CACAATCAAGATGTAAGACG TTCTCTATCA CCCCAGAAAG 12751 TTCCCTCATC CACTTTGCAT TCAGGCCTCCAGATCTAGGC AACCACAGAT 12801 CTGCTTTCTG ACACTGTGGA TTAAACTTTG CCTGTTCCAGAATTTCATAT 12851 AAATGGATGT GTATAGTATG TACCCTTTCG TGTCTGGCTC CTTTCCCTCA12901 GCATAATGTT TCTGAAATTC ACCCACATTG TTACATGTAT CAGTAGTTAA 12951TTCCTTTTTA TTGCTGAGTA GTAATGCCAT TGTATGACTA TGTATGACAT 13001 TTGTTAATCCATTTTCCCGT CAGTGGATAT TTGGGTTGCT TCCAGTTCTG 13051 GGCAGGTATT CATTTGCTAGGGCTGCCATA TGCTTGCCCT CTGGCCTCCC 13101 AAAATTTGTG TCCTTTTCAT ATGCAAAATACATTCACCCC CTCCCAACAG 13151 CCCCAAAACT CTCTTTTTTT TTTTTTTTTG AAACAGAGTTTTGCTCTTGT 13201 TGCCCAAGCT GGAGTGCAAT GGTGTGATCT CGGCTCACTG CAACCTCTGC13251 CTCCCGGGTT CAAGAGATTC TCCTGCCTCA GCCTCCTGAG TAGCTGGGAT 13301TACAGGCATG CGCCACCACG CCTGGCTAAT TTTTTATATT TTTAGTAGAA 13351 ATGGGGTTTCACCGTGTTAG CCAGGCTGGT CTTGAACTCC TGACCTCAGG 13401 TGATCCGCCT GCCTTGGCCTCCCAAAGGGC TGGGATTACA GGCATGAGCT 13451 ACTGCACCTG GCTAGCCCCA AAACTCTTAACCCATTTCAG CATCTACTCT 13501 AAGTCCAAAG TCTCATCTAA ATCAGGTATG GGTGTGACTGGAGGTGTTAC 13551 TCATCCTGAG GCCAAATTCC TCTCCACTTA TGAACCTGTG AAACCAGACA13601 GGTTATGTGC TTTGAAAATA AAGTGATGGG ACATGCATGG GATAGACTTT 13651CCCATTCCAA AAGAGAAAAA TAGGAAAGAA GGAAAGAGTG ACAGGTCCCA 13701 AGCAAGTCTAAAACCTCGCA GGGCAAATTC CATTAGATTT TAAGTTTCAA 13751 GAATAGCCCT CTTTGGCTCAGTGCTCTGCC CTTTGGGCCC ACTGGGGCGG 13801 CAGCCCTATC CCCTTTGCCC TGGGTGGTGACCCTACCCTC GAGTCACTGG 13851 TTAGCAGCAG CCTAGCCTGC TGAAACTAAG GAGGGGACAGTGTTGCCTCC 13901 AGGTCTTTGG TGGCAGTGAC AACCCTGCTG ATCTCTGAAT CATCTTCCAG13951 GAAATTTTTC CCTATACTTG AAGGATATTG CGTGTTCACA GCCAAATAGC 14001TCCAGCTCTT GTCCCTTTCT TTAGAATCCC AGAAGTCCAA CAGCCTTCCT 14051 TCATTCTGTCCCATCTCTGT CCCCTTTAGT CAAAGCTGGA AGTGCCTCTG 14101 CTGGTATAAT CCCATCAGTATGTCTAATTT CTGCTTAAAT GGCTGATTAA 14151 GTCTATGAGT TGCACCTCTG ATCTCTTTATCAAAAGGTTG TTCTAGCCAC 14201 AACCTTAGTG TCCTCCCCAG AACATGCTTT CTCATTTTTTTTTTTGCAAT 14251 GTGGATAGGC TGAAAATTTT CCAAAGCTTC AAGTTCTAGT TCCTTTTGGC14301 TTACCAATTC TTTTCATATA TCTCTTCTCT CACATTTTAC TATAAGCAGT 14351AAGAAGAAAC CAGGTTGTAC CTTCAGCACT TTGCTTAGAA ATCTCTTCTG 14401 CTAAGCATCCAAGTTTATGT CTTTTAAATT ATCTTTTTGT TATTTATTTT 14451 ATATTATCAT TTTTGAGATGGCTAGCCAAT GATCTTTTAA CTTCTAATTT 14501 CTGCAAAACA CTAGAAGACA ATTCAACCAGTTCTTTGCCA CTTTATAACA 14551 AGGATCACCT TTCCTCCAGT TTCCAATAAC ACATTCCTCTTTTCCACCTG 14601 AGACCTCACC AGAATCACCT TTAATGTCTA TATTCCTACC AATAGTCTTT14651 TTAAGGCAAT ATAGGCTTTC TCTAACATGC ACTTCAAACT TCAAGATTCT 14701ACCCATTATG CAATTCCAAA GCCACTTCCA CATTTTTAGG TATTGATTAC 14751 CTCAGCACCTCATTTCTGGT GCCCAAATCT GCACTGGTTT GCTAGGGCTG 14801 CCATAACAAA GTACGACAGTCTGGGTAAAC AACAGAATTT TATTTTCTCA 14851 AAATTCTGGA GGTTGGAAGT CCAAGGTCAAGGCGTTGCTA GGTTTAGTTT 14901 CTCCTGAAGC CTCTCTCCTT GGCTAGCAGA TGGCTGCCTTCTTGCTGTGT 14951 CCTCACGTGG CTTTTTCTCT GTGTGTGTTC ACTCTGGTAT CTCTTCCTCT15001 TCTTACAAGT ACACCAGTCC TACTGGATTA GGGCCCCAGC CTTATTACTT 15051CATTTAACCA TAATTACCTC TTTAAAGCTC TTATCTCAAA ACACAATACC 15101 ACTGGGGATGAGGTCTTCAA CATATGAATT TTGGGGGAAC TCAATTCGTC 15151 CATAATAGGG CTATTATGAATTAAGCTGCT GTGAACATTC ATGTACAAGT 15201 CTTTGTGTGG ATATGTTTTC ATTTCTCTTAGATAAAGATC TAGGAGTATC 15251 AGCCTGGGCA ACATAGTGAG ACCCCATCTT TACAAAAAATTTTCAAAATT 15301 AGCCAGGCAT GGTGGCGTAC ACCTGTAGCC CTGCCATCTC AGGAGGCTGA15351 GGTGGGAGGA TCCCTTGAGC CCAGGGGTTT TAGACTGCAG TGAACTATGA 15401TTGCACCACT GCACCCCAGC CTGGGTGACA GAGTGAGACT CTGTCTCTAA 15451 AAAAAAGAGAGAGAGGGGAG GAAGGAAAGA AGAAAGAGAG GGAGGGAAGG 15501 AGGGAGGGAG GGAGGGAGAAGAAAAATGGA TCTAGGGTTA AGATTTAGGA 15551 GATTAGGTAA TGAATGTGTA CTATTACAGGGAACTGTCGA GCTGTTTCCA 15601 AAGTGACTGT ACCATTGTTC ATTGCCACCA ACAATACATGAGAGTTCTAG 15651 TTACTCCATG TGCTTGTTAC ACTTAGTATT ATCAGTCTTT TTCATTTTAA15701 CCATTCTAGT GAGTATGTAG TAGTATTTTA TTATGGCTTT AATTTACAAC 15751TCCCTAATGA TGAATGATGT TGAACATCTT TTCATGTGCT TATTGGCCAT 15801 TCATATATCTTTTGTGAAGT GACTATTCAA ATATTTTTCC ACTTTTTATT 15851 AGGTCATTTA TTTTCTTATTATTGAGTTAT CTATGAATAC AAATCCTTTA 15901 TCAGTGTATG TATTGTGATT TTTTTCCCCAGTGGCTGGCC TTTTCATTTT 15951 CGTTAGGCTT TTTTGGTGGG TTTTTTTTTT TTTTTTTGGAAGAGAAAAAT 16001 ATTTTAATTT GATAAAATCC AGTATATCAG GTGTTATAGA CTGAATTATA16051 CTCTACCCCA CAAATTCATA TGTTGAAGCC CTAACCTCTA AGTGACTATT 16101TGGAGATGAG CCTTTAAGGA GGTAATTAAA GTAAAATGAG ATCATAAGGG 16151 TGGGCCCTAATCTAATAGGA CTGGTGTCTT TATAAGAAGA GGAAGACACC 16201 AAGAGCGCAT GCACACAGAAGAACGGCCTT GTGAGGACAC AGCAAGATGA 16251 CGGCCATCTG CAAGCCAAGG AGAGAGGCCTCAGTAGAAAC CAAACCTGCT 16301 GATGCCTTGA TCTTGGACTT CCAGCCTCCA GATTTCTGTTGCTGAAGCCA 16351 CCCTGCCTGT GGTGTCTTAC CATGGCAGCC CTCACAGACT AATATATCAG16401 ATTTTTTTCC TTCAACAGTT AACGCTTTTG GTGTCCTAAG CAATATTCGC 16451CTGACCCAGG GTCATGAAGA TTTTTCTTCT ATGCTTTCTT CTGGAAGTTC 16501 TATAATTTTAGCTTTTACAT ATTTTTTTAA CTTTCCTTCT TCTTGCCTTC 16551 TGTTTCTTTT AAGGCATCATCTATTGTGTT AATTTGTTCT TGTATTCCTT 16601 CTGATTTATT CTTCACTTCT GAAATGAATTTTGCTTTTTA AAAATATATA 16651 TAATTCTTTT CTGTGTCTGA GTTTTTCTAA TTAGGTTTTATGTGGTTTTT 16701 TCTTGTCCTG CATCACTTTT TACTGTCTTT TGCCCATTTT GAAGTATCAG16751 GTTCCAGTTT TGATCTGTTC ATGGATATGT TTTTGTGACA TGTTTCTTCT 16801GGCTTCTTAT CATTTATTGC TTAGCTTATT AATTTCTATT CTTTCTTATT 16851 TTCTATTATAAGTATTTAAA GCTATATGTT TTCCTCTAAG TATTACTTAG 16901 CTGTCTTATA CGTTTTCATTTGTGTTATTT GGTGATCATT CACTTTCAGC 16951 TATTTATTAA TTTCCATTAT AATTCTTTCATCTATGGGTT GTTTTAAAAA 17001 ATATTTTTAA GGCCAGGTGT GGTGACTCAC ATCTGTAATCACAGCACTTA 17051 GGGAGGCTGA GGTGGGAGGA TTGCTTGAGG CCAGAAGTTT GAGACCGGCC17101 TAGGCAACAA AGTGAGACCC CCTCTCTACA GAATATTTTT TTAAAATTAG 17151CTGGGCCAGG CGTGGTGGCT CATCCCAGCA CCTGTAATAC CAGCACTTTG 17201 GGAGGCCAAGGCAGATGGAT CACCTGAGGT CAGGAGTTCG AGACCAGCCT 17251 GGGCAACATG GTAAAACCCCATCTCTACTA AAATATAAAA ATTAGCCAGG 17301 TGTGGTGATA GGTGCCTGTA ATCCCAGCTACTTGGGAGGC TGAGGCAGGA 17351 GAATTCTTTG AACCCAGGAG GAGGAGTTTG CAGTGAGCCGAGATTGCACC 17401 ACTGCACTCC AGCCTGGATG ACAGAGCGAG ACTCTGTCTC AAAAAAAAAA17451 AGAAAAGAAA ATTAGCTGGG TGTAGTGGCA GGTACCTGTG GTCCCAGTGA 17501CTCAGAGACT GAGGCAGGAG GATCACCTGA GCCCAGGAGT AGAGGCTGCA 17551 GTGAGCTATGTTTGTGCCAC TGCACTCCAG CCTGTGCAAC AGAGCAAGAC 17601 GCTGTCTCAA AAAATATATATTTTTTTAAA TTTTCAAACT TCCTTTAGTT 17651 CTCTTTTTGT TATTAACTTT TAACTGAATGTTTTGCAATC AGAAGAAATA 17701 CTTTATGAGA TACCTATTCT TTAAAATTTC TTAAGAATTGCTTTGTGTTA 17751 ATATTTTGTT AATAGTTCAC ATGTGGTTCA ACCAATTTGT TTAGTTAGTT17801 CTGTATATGT TCATTAGACC AACTTGATAA CTGTGTTGTT CTTTATTTAT 17851TTATGTATTT ATTTTTCTTT GTCTATTCAT CAATTGCTGG GTGAGATGTA 17901 TTAAAATTTCTTGTTGTAAG TGTGGCTGTT CACTTTCTAC CTGTAGTTTG 17951 TCTGTTTGCT TTATAGAGGGTGAAGTTGTT TAGTAGGCAC ACATAAGTTA 18001 GAATTTTTCT GTCTTCCTGG TGAATGGAATCATTTATCAT TATCTAATGT 18051 TCTTTTCATC TTTAGTATTG CTTTGGACTT GGAAGTCTGTATTTTGTCTC 18101 CTGTTAATAT AACTACACTG GTTCCTTTGG TGTGAATATT TGCATAGTAT18151 AACATTTTCC ATGAAGAAAC AAAACAGAGG AATTGGTTCT TTCTCAAAAT 18201CTGATCTTTG TGTCAGCCCC CATCTCAGCC TTCTCCATTC ATCCTTGGTC 18251 ACTCCCCAAACCCAGGAGCA ATCCTTGATT CTCCTTTTCC CCACATTCTA 18301 CATCCAATCC GTTAGCAAGTTCTATTAGTT CTATTATTAC CTCCAAAATA 18351 GATATTGAAT CCAGCCCTTT CTCACTGTCTCCACCATCAT CCTGTCTCAC 18401 ATCCCTACCA TGGCCTCCTT GCTGGTTGAC CAGAGTGATCTTGTAAAAAC 18451 ATGTTAGGCC AGGCACGGTG GCTCCTGCCT GTAATCCCAA CACTTTGGGA18501 GGCCAAGCGG GTGGGTCACC TGAGGTCAGG AGTTGGAGAC CAGCCTGGCC 18551GACATGGTGA AACCCTGTCT CTACTAAAAA TACAAAATTA GCCAGGTGTG 18601 GTTATGCTGGCCTGTAATCC CATCTACTCG GGAGGCTGAG GCAGGAGAAT 18651 CACTTGAACC CAGGAGGCGGAGGTTGCAGT GAGCCAAGAT CATGCCACTG 18701 CACCCCAGCC TGGGCAACAG AACAAGACTCCATCTCAAAA AATAAAAATT 18751 AAAATAAAAT GTTAGGCTCC CTGGGTCTCT GGCTTAGTCCATTTGTACTG 18801 CTTTAACAAA ATACCTTAGA ATGGTGTAAT TCTAATAATT GCTATTAATA18851 AATAATAGCA ATTAATAAAT AATAGCAATT TCCTTCTCAC AGTTCTAGAG 18901GCTGGGAAGT TCAGGGTCAA GGTGGCACCT GACTCCGTTC TGGTAAGGGC 18951 GGCTCTCTGCTTCCAAGATG GTGCCTTCTC GCTGCGTCTT CGCATAGCGG 19001 AAGGGCAAAC ACTGTGTCCTCACGTGGCAG AAGAGATAGA AGGGCCAGGC 19051 AGCTCTCTGA AGTATCCAGG TTGGAGTCATGGACCTGCAT GTTCCCCTCT 19101 GACATCCACA GAGTACCTAT CATGGTCCTT GGCATGCAGCAGGTGGCCCA 19151 TAAACGCCTG AATGAACAAA CATATAGTAA TGGTCGCTAG TACTAGGAAT19201 AGCAGCCACC GCAACAGTCC TGTGAGGGAG GCATTACAGA TGAGGAAACT 19251GAGGTTTAGG GGCAAGGACC TGCCCATGGT CCCAAAGCTA GGGAGGGACA 19301 GGGCTGGGATTCCCACTCCC ATCCATCTGG CTCCAGAACC TGAGCTCCTG 19351 ACCAGGCTGT TCTTATCCTGTCTCAGCCAG TGGCTGCCTG TCTGGACGGA 19401 TGGACCTAAA GTCAGTCCAG CCAAACAGAGGGAAGCATGA TCAACTGTTC 19451 TCTAAGTTCC CTGACCCGGA GAGGCTGAGT CCATGGCCCAAGCTCTCCTC 19501 TCTCCTCCCC CAGCTCTCCC ACCCGTAGAC GGTGGCGCGA AGTGGAAGAG19551 TGTGCGGGAA CCAAGGAGCT GCTATGTTCT ATGATGTGCC TGAAGAAACA 19601GGACCTGTAC AACAAGTTCA AGGGACGCGT GCGGACGGTT TCTCCCAGCT 19651 CCAAGTCCCCCTGGGTGGAG TCCGAATACC TGGATTACCT TTTTGAAGGT 19701 AGGTCTGTGG GTAAGGGACTGAGTGGAAGG CTGTCCATCC CATCGGGGAG 19751 CTGTGCTCAG TGCTCAGTGG TTCTGTTCTCCTGACCATCT GTCTCCCACT 19801 TCCCCAAAGC AGAGGGCAGC TCCCTGGGCC AGGCCCTTTGAGATGGGGTG 19851 TGGGACCAGC AACAGCGAGG GACCATGTCT GGTAGCCTGT CAGGGAGTTA19901 GGGGAGCTCC AGCCAGCACC AGCAATCTCA CGTGCACCCT CTGCTAACAA 19951TGTTCATTAT TTTCAGTTGA GCACCATTTT GGTCATGGAC TACACAAGGC 20001 ACTTTATATGCTTATTCCTA TTTTTTTATG TTCAGCTTCT CTCCTTAAAA 20051 ACAATGTTTA AAACCAATTCTGGGCCAGGC GTGGTGGCTC ACGCCTGTAA 20101 TCCCAGCACT TTGGGAGGCC AAGGCAGGTGGATCACCTGA GGTCAGGAGT 20151 TTGAGACCAC CCTGGCCAAC ATGGCAAAAC CCCGTCTTTACTAAAAATAC 20201 AAAAATTAGC CAGGCTTGGT GGCAGGCACC TGTAATCCCA GCTACTCGGG20251 AGGCTGAGGC AGGAGAATCG CTTGAACCCA GGAGGCGGAG GTTGCAGTGA 20301GCCAAGATCA CGCCCCTGCA CTCCAGCCTG GGCGACAGAG CGTCTCAAAA 20351 GAAAAAAATTAATAAACAAA GAAAAAAAAA CAAATTCTGT TTGCAAAAGT 20401 ATTTTCTATA CACTGTAGAAATTTGTGGGG TGTGGGGGGG TAAAGATGAT 20451 AGAAAAAAAA ATGTCCCATG CTTACTGGCAGAAATCATGT ATTGACATTG 20501 GGTGAGGAGG GCACTTTTTT TTTTTCAGTC TATTTTTAATCTTCACAGCA 20551 AACTTGTGAG GTTCATTTCC ATCAACCTGA GACTCACAGA AGCTAAGAAA20601 CTTGATACCG CTAGTAACCA GTGGACTTGA TACCGCTAGT AACCGGTGGA 20651CATAGATGTG AACTGGATCT TTCTGACCTC GGGCAGGGCC GGGTAACAAG 20701 GGGAGGATAAATGCCCAGAC AGTGTCCTCA GAGAGCTGAG AGCTGTAACT 20751 TGCTGCCCGG GCTTCTCACAGTGTTCAAGG ACAAAATAAG GCTTTAAGAG 20801 AGAAGAGGGA CAGACTGATT GCAGGGCAGCAGGAAGAGAT GGTAGAGAAG 20851 GAAGAAGAGA TGATTCGTGT GGAAAGAAGC TGGCTCGGTGGATGGATAAA 20901 AGAAGGGAAG GACAGATGGG TAAGAAGAAA GGGAGGATGG AGGGGATGGA20951 GGAGGAAGCA ATGGAAAAAT GGGAAGGAAG GAGGTTGGAT GGAAGGATAG 21001ATGCCTATTA GGAAGGAAAT ATGTGTGGAT AGAGAGATGG AGGATAGGAA 21051 GTATGTTAGTCAAGGTTCTC CAGAGAAACT GAACCAATAG GATATATACA 21101 GATACACTAA GAGGAGGCCAGCCGGGCGCG GTGGCTCAAG CTTGTAATCC 21151 CAGCACTTTA GGAGGCCGAG GCGGGCGGATCACGAGGTCA GGAGATCAAG 21201 ACCATCCTGG CTAACACAGT GAAACCCCGA CTCTACTAAAAATACAAAAA 21251 AAAATTAGTT GGGCGTGATG ATGTGCGCCT GTAGTCCCAG CTGCTGGGGA21301 GGCTAAGGCA GGAGGATGGC GTGAACCCAG GAGGCAGAGC TTGCAGTGAG 21351CTGAGATCGT GCCACTGCAC TTCAGCCTGG GTGACAGAGC AAGACTCCGT 21401 CTCAAAATAAATAAATAAAT AAATAAAAAG AGGCCAGCCA TGGTGGCTCA 21451 CACCTGTAAT CTGAGCACTTTGGGAGGCCG AGGCGGATGG ATCATTTGAG 21501 ATCAGGAGTT CAAGACCAGC CTGGCCAACATGGTGAAACC CTGTCTCTAC 21551 TAAAAATACA AAAGTTACCC GTGTGTGGTG GCACACACCTGTAGTCCCAG 21601 CTACTCAGGA GGCTGAGGCA GGAGAATTGC TTGAACTTGG GAAGCAGAGG21651 TTGCAGTGAG CTGAGATCAC GACACTGCAC TCCAGCCTGG GTGACAGAGC 21701AAGACTTTGT CTCAAAAAAA AAAAATTTAT AATAAGAGGA GATTTATTAT 21751 GGGAATTGGCTCATGCAATC ACAGACACAA AAATGTCCCC CAGCATGCAG 21801 TCATGGGCTG GACAACCAGGAAAGCTTGTG GTGTGATTCT GTCTGAGTCT 21851 GAAGGCCCAA GGCCAGGGGA GCAGTGGTGTAACCCCCAGT CCGAGGCCAC 21901 AGGCCCGACA ATCAGAGGGG CCACTGATAT AAGTCCCAGAGTCCAAATGC 21951 CGGAGAACAG GAAGCTCCAA CGTCCAAGGA CAGGAGAAGT TGATGTGCCA22001 GCTCAGGAAG AGAGAATGTG AATGTGCCAT TCCTCCTCCA TTTTTTGTTC 22051TCTTTGGGCC GTCAGTGGAT TGGATGATGC CTGCCCACAC TGGTGAGGAC 22101 AGATCATCACCAAATCTGCC GATTAAAATG TTAATCTCTT CTGGAAAAAT 22151 CCTCACAGAT GGGCCCAGAAATAATGTTTT ACTGTCTACC TGGGTATCCC 22201 TTAGTGCAGC TAAATTGACA CATAAACTTAACCATCACAG GCCAGGCACT 22251 GTGGCTCACA CCTGTAATCC CATCACTTTG GGAGGCCAAGGTGGGAAGAT 22301 CCTTTGAGGA TGAGGTAGGC AGATCACTTG AGCCTAGGAG TTCAAGACCA22351 GCCTAGGCAA CATAGGGAGA CCTCGTCTCT ACAAAAAAAA AAAAAATTTA 22401AATTCGCTGG GTACGGTGGT GGGCACCTGT GGTCCCAGCT ATCTGGGAGG 22451 CCAAGGTAGGAGGATGACTT GAGCCCAGGA GGTCAAGGCT GCAGTGAGCC 22501 ATGATTGTTC CATTGAATTCCAGCCTCGGT GACAGAGCAA CACCCTGTCT 22551 TAAAGAAAGA AAAAATTTAA CCATCACAGAAGGCAGAAGA AAAGGCAGAT 22601 GGGTGGATGA GATGGGTGGG TAGATAGTAT AGAAGAAAAGCGGGACATCC 22651 AGGCAGGGAA GGAAGGGCTG GAGCGAAGGA GAAGCAAGGA AGGAAGGAAG22701 GAGAGACAAG AAGGAAGGAT GTGTAGAAAG GTGGAAGAGA AAAGAAGAAT 22751GGATGTATGG GAAGAATGGA TGAGTAGGTT AGAAGGCTCA CTGGCTAGAT 22801 AAAAGGTGAGAAGTATAAAT GAATAATAAG AAAGGAGGCA TAGGAAGAAA 22851 AAAATATTGG TTAGAAAGGATGATTGAGAA GAAAGGGTGG TTGGGAAGGA 22901 AGGAAGGAAG GATGGATGGA TGGATGGATGGATGGGAAGG AAAGGAAGGA 22951 TAAGAAGGCA GACAGGAAGG CTCTCTGGCT AGAAGAATGGCAGACAAACC 23001 ACAATAATTG CTGAATGGGT AGGAATAAGA CATTAGAAGA ATAAAGGGAA23051 AGACACAAAG ATATTTAAAA TGTTTTCATT AATTTTTTGC CTCCTCCCTG 23101AATTTCTCCT GATTCTTCAG CCCCACATCC CAAGCCAGGG TGATCCTTCC 23151 TGCCTTTACACTCCCTCCAC ACTTTTTCTG CTCTCATATG TGGCCGTGGT 23201 CACTTTCTTT TGGTAGTTTGCATATTTCAT TTACCCCAAA CTTTCAGCTC 23251 CTGAAGGTCA GGATACAAGG AGGCCTCATCTCCGCATTCC CCTCAGCTCC 23301 CTTCCTGAAG CTTGATACCT AGTCAGTACC CAGTGGATGTTTCCTAAACA 23351 TGTAAGTAAT GACATCATGA AGAAGCCACA TGTTTACCTT GACCACAAAC23401 ACAGGGCAAA GGTGACTAGT GTGGTCAGAG ATCCCTGCTG GCTGGGAATC 23451AGGGAAGGCT GCATGGAAGA AGTGGCATTT TAGTTAGAAC TTGAAAGGTG 23501 GTGTATTTAGTTTTCTCTGG CTGCCATATT CCTTGTCACA TTGCCCTCTC 23551 CATCTTCAAG CCACTGGGCAAGGCTAGAAG GCCCTCAACA GACTATCGGT 23601 AGGAATGTGG AAGTTGAAGA CTCAGAGTGCAGAAAGAAAC AAGTAGCATT 23651 TTAGAGAAAA GCTAAATCCC CTCCAAGAAT ACCTCAATCATCGTGAAGAG 23701 CCTGTTAGTA GACGCACTAA CACTCAAGGC ACTGCTTCAC AAGGTAAGGA23751 ACGTGTAATT GAAAACTTGA GAAAGGAAGA AACTTGTTCT GTACTGGCAG 23801AAAGCTTAGC AGAATTGTGT CCTGCAGTCA TATGGGACAC AGAGCTTGTA 23851 AATGATGAATTTGAATGCTT ATCCGAGAAG GTTTCCAAAT AAAATGTGGA 23901 AGGCACGGCC TGGTTTCTTCCTGCCTCTTA TAGTAAAATG CAAGAGGAGA 23951 GAGAGAAAAT GAGGGAAGAA CTTAAACAGAAAGGAACCAG GACTTGATGA 24001 TTTGGGAGGT TCTCAACCTA TGCAAAAAAC AATAAAATTAAGAGATTGTA 24051 GCTGGGCACA GTGGCTCATG CCTGTAATCC CAGCACTTTG AGAGTCCGAG24101 GCGAGCAGAT CACCTGAGGT CAGGAGTTTG AGACCAGCCT GGCCAATGTG 24151GGGAAACTCC GTCTCTACTA AAAATACAAA AATTAGCTGG GTGTGGTGGC 24201 GGGCACCTGTAATCCCAGCT ACTCAGGAGG CTGAGGTGGG AGGATCACTT 24251 GAACCCAAGA GGCGGAGGTTGCAGTGAGCC AAGATCATGC CACTGCACTC 24301 CAGCCTGGGT GGGTGACAGA GCAAGACTCCATCTCAAAAA AAAAAAAAAA 24351 AAGAGATTGC TCCCAAAAGT GTGACATAGA GAAACAGCCAAGTATGTGAT 24401 TATACCAAAC TTCAGGAAGA TAAAAGATCA AAGTACTCAG TCGCTCAAAA24451 GGCTCTTTGA AGAGATTAAG ATTATAACTC ACAGTCCCCT TCAATCAAAC 24501CAGGGGACTT CTAGGAAGCT GAACAGCATT GTCCCTCAGC CATATCAGCT 24551 GGAGCCAAAAGTAGAGAAGG GCTTATCTGA AAAAAGGATC TGTGGACCTG 24601 GCTTTTATCT AATAATGCAGTGGATTCCCC CATGACATCC ATAGGAGACC 24651 CGTAAAGTTC CTGAGACGTT TACATCCACAGAAACACTGT TAGCTTGGAT 24701 TAAATGGAAC ACAGAGAGTA TGAAATCAAA GAAGGCTGTTGGACTCTCCA 24751 GTTTCTACTG TTGAGATGCA GACTGGTAAA ACTACTTAGC TGCAAACACC24801 TGCTACCTTT AGTGAAAAGG AAGGATATCT CAGACGGTGA AACCAGAAGC 24851TCAAAGGGCA GTGCTAAGAG CGAAAGAGAA TTCTTCCCAG GCCTTGAAAC 24901 CTAATGGAGTTTTCTTGGCT GGATTTTCAA ACTGCATTGG ACCATGACCT 24951 GATTGTCCCT TTCATGTCCCCATGCTTGAG CCAGATTGTC TGCAACTGTT 25001 ATCCTGTGCC TGTCCCACAT TTTATGTTGGGAGCAGAAAA CTTTAGTTTT 25051 GCTGGCCCAC AGATAGAGAG AAACTGTACC CCGAGAGTTGTACTGACTGG 25101 ACTATGCCCA GAGTCTATTT GACTCTGACT TAGATACTGT TGATTTGGGA25151 ATTTGAGTTG ATGCTGTAAT GAGATGAGAC TTTGGGGGAC ATTGGGATGG 25201AGTGAATGGA TTTTGCATTT GAAAGAGATG TGGGTTGGGT AATCCTAGCC 25251 CACACCTGTAATCCCAGCAC TTTGGGAGGC CGAGGCAGGC AGATCACCTG 25301 AGGTCGGCAG TTCGAGACCAGCCTGACCAC CATGGAGAAA CCCCATCTCT 25351 ACTAAAAATA CAAAATTAGC CAAGCATGGTAGCACATGCC TATAATCCCA 25401 GCTACTCGGG AGGCTGAGGC AGTAGAATCG CTTGAACCCGGGAGGCAGAG 25451 GTTGCGGTGA GCCGAGATCA CGCCATTGCA CTCCAGCCTG GGCAACAAGA25501 GTGAAACTCC ATCTAAAAAA AAAAAAAAAG AAAGAAAGAG ATGTGGATTT 25551TGGGTGGGGG ACAGAGGGAA GACCATGGTA GGCAGAATGA TCCTCTAAAG 25601 GTGCTCTGCCCTAATCCCCA GAAGCTAAGA ATATGTTAGA TGTCAGTATT 25651 GCGTGGCAGT AGGAATCTTAATTAACGTTA TAGACTGTTA TGGTTTGAAT 25701 GTCCCCTCTA AAACTCCTGT TGACATTTAATCATCATTGT GATTGCATTA 25751 AGAAGTGGCC CTGTTAAAAG GTGATTTAGT CCTTAAGAACGCTGCCCCCG 25801 TGAATAGATT AAGGTCAGTC TTGCGGGAGT GTGTTTATCA AGAATGGATT25851 GTTAAAAAGT GAGTTCTGGC CAGGGGCAGT GGCTTATGCC ACTCAGCACT 25901TTGCGGGGCC AAGACTTGAA GTCAGTTGTT TGAGACCAGC CTGGCCAACA 25951 TGGTGAAAGTCTGTCTCTAC TAAAAAATAC AAAAAGTGTC CGGGAGTGGT 26001 GGCGGGCGCC TGTAATCCCAGCTGCTCAGG AGGCCGAAGC AGGAGGATCG 26051 CATGAATCCG GGAGGCAGAG GTTGCAGTGAGCTGAGATCG CCCCGTTGCA 26101 CTCCAGCCTG GGTGATAGAG CAAGACTCTG TCTCAAAAAAANNNNNNNNN 26151 NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN NAAAGAAAGA26201 AAGAAAAGAA AAGAAAAGTG AGTTCTGCCC TCTCTTGCTG GCTTACTCTC 26251ACCCTCTCTT GCCCTTCCAC CTGCCACCAT GGGATGACAC AGCACAAAGG 26301 CCCTCACCAGATGCCAGTGC CATGCTCTTG GACTTCCAAG TCTCCAGAAA 26351 CATGAGCCAA ATACACTTCTGTTCATTATA AATTACCCAG CCTGTGATAT 26401 TCTGTAATAA CAACACAAAA TAGACTGAGACATAGATCTT CAAATAGTGA 26451 GGTTATCCTG GATAATCCAG ATGGGCCCAA TCTAATCCCATGAGCCTTTA 26501 AAACTTTCTC CAGATGGAGG CAGAAGAGAA GTGGCAGAAG GGGAAGTCAG26551 AGAGATTTGA AGCATAAACA GGACTCCATG GTGCCGTTTC TGGTTTGACG 26601ATGGAGTGGT AACGTGATGA AAAATGTGGG TGCCTTCCGG AGCTGAGAGG 26651 CTCCCACTAACAATCGGCCA GGAAACAGGG ACCACAGCCC TACAGCCACA 26701 AAGAACTAAG TTTTGCTGACAACCCAAGGG GGCTTGGAAG TGTCTTCTCC 26751 CCCATCGGTT CCAGATGTGA GACCCAGAGCGAAGGAACCA GCTGAGCCCA 26801 CCTGGACTTC TGACCTAGAG AACTGTGAGA TAATAAGTTTGTATCATTTT 26851 TAAGGCACTG TGTGTGTGGT AATTTGTTAT GACAGCAATA GAAAATGAAT26901 CCAGATGGGC AGGATCTGCC AGGCCAGTGA CATGTGGAGG GCACCCAGGC 26951GGATGGGATG GCATGAGAGA AGGCAGGTCA GCAATGAGCT TGCCCAGGTC 27001 ACCTCTCCTCTCTAAGCCTC AGTTTTCCTC TCTATGAAAT GAGAGTAGTG 27051 ATATCTCCCT CCCAGGGTCAGTGCAAGGCT GAAATAACAG ATTATAAGGT 27101 GCTAGGTGCA CAAGAAGTGT TTGAAACATGCTAGTTGCTT TTCCATTTCC 27151 AAGAGAGCTC TCTGGTCTTG GGGGATGGAG GCAGTGCGGCCCCTCGGGAT 27201 TACTGACAGG TCCTGCTCTG TTTCTGCAGT GGAGCCGGCC CCACCTGTCC27251 TGGTGCTCAC CCAGACGGAG GAGATCCTGA GTGCCAATGC CACGTACCAG 27301CTGCCCCCCT GCATGCCCCC ACTGGATCTG AAGTATGAGG TGGCATTCTG 27351 GAAGGAGGGGGCCGGAAACA AGGTGGGAAG CTCCTTTCCT GCCCCCAGGC 27401 TAGGCCCGCT CCTCCACCCCTTCTTACTCA GGTTCTTCTC ACCCTCCCAG 27451 CCTGCTCCTG CACCCCTCCT CCAGGAAGTCTTCCCTGTAC ACTCCTGACT 27501 TCTGGCAGTC AGCCCTAATA AAATCTGATC AAAGTATGATGACCTACAGG 27551 AGGCCTGCTT GCCAAGTCAA CAGATTCAGT ACAGAAAAAC TGAAAAATAC27601 AGATAAGCTC TAAGAAGCAG ACCAAAAGTA CCCAGAGATG ACCGCACATC 27651ACTCTGGTGT ATATCCAATT TCAGATTTGT TTTCTGTGTA TGCATGTGTG 27701 TATAGCTGCATTTATTTATG GCAAGGGCTG GCAGACTTTC CCGAAGAAGG 27751 CCAGATAGTC GATATGTTTGGCTTCATGGG CCGTATGTTC GCTCAGGACT 27801 ACTCAACGCT GCAGTTATAG CACAAAAGGAGCCGTAGCCT ATACGTAAAT 27851 GAATGGGCAT CGCTGGGTTC CAGTAAAACT GTTTACAGGCCAGGTGCGGT 27901 GGCTCATGCC TGTAATCTCA GTACTTTGGG AGGCCGAGGT GGTGGGAGGA27951 TTACCTTAGC CCAGGAGTTC AAGACCAGCC TGGGGAACAT GGTGAAACAT 28001TATCCCTACA AAAAAAAAAA AAGCTGGGTG TGGTGATGCA TGCTTGTGGT 28051 CCCAGCTGCTTGGGATGCTG AGGCAGGAGG ATCGCTCGAG CCCAGGAAGC 28101 AAGGCCACAG TGAGCCATGATCGCACCACT GCACTTTAGT CTGGGCAACA 28151 GAGTGAGACC TTGTCTCAAA AAAAACAAAAAATAAAACTT TTTACATAAA 28201 CAAGTGGCCA ACCAGACTTG GTCCCTGGGC CTCTGCTCTTGAATGTTCTT 28251 GCTTCCACTA AAGTAACATT CACACTCCCG ATTTTTGCAT ACTCTGGGTT28301 CTGGGGAATA TAGATCCGAA TCCAGCGTGG TTCCTGCCTT CAAGAACCTC 28351ACAAATATTC TAGACCAGCA CTGCCCAATA GAAAGAAATA TAATGCAAGC 28401 CACATGTGCAGTTTTAAGTG TTCCATGTTA AATTAAGTAA AAAGAGACGG 28451 GTAAATCGAA TTTTAATAACAGATTTTACT TCATCCAATT GAATGGTATC 28501 ATTTCAATGA GCAATTCTGA TAGTGATTGAGATCTTTTAC ATTCTTTTTC 28551 ACTACGTCTT TAAAATCTGA TGTGTGTTTT GTACTTGGAACACTTCTCAG 28601 TGTGGACCAG ATGCATTTCA CATACTCAGT AGTCACGCGT GGCCAGTGCC28651 TTCCATACCA CACAGTGCAG CATCTGTAGA GGTTTCCTCC ACTGCTGATA 28701GACTAGGAGA CCCCAAGATG GAAAGCCTGA AGAATCTGCT CCTTGAAGTA 28751 GGGACCTTAATGGGGTGCAC GCCAGGGCGA CCCCAAGTGG TAGGCTGCTT 28801 TTGAACCATG GCTATCCCTACCTCTAGACT CAGCTGAAAA GAACTCAGGT 28851 AGTCTTGGGA AGTGCTTCCT CAATGCTTAAACTTTAATGC AGGAAAAGAA 28901 TAGAAAGTTC AGGCAAGGAG GGAGGATCAC TTGAGGCTGGGAGTTCGAGA 28951 CCAGCCTGGG CAACAGCAAG ACCTTGCCTA TACAAAAAAT AATTTTAAAA29001 AATTACCCAG GTATGGTGGT GTGGATCTGT AGTCCCTAGT TACTTGGAGA 29051GCTGAGGTAG GAGGATCGCT TGAGCCCAGG AGTTTGAGGC TGCAGTGAGC 29101 TGTGATCACACCACTGCACT TTGGCCTGGG TGACAGAACC AAACCCTATC 29151 CCCTACAAAA AAACAAAAAAAAAAAACAAA AAAAAACACC CTACCATGTC 29201 TGCCAACCCC ACTCTGTCCT GGCTGTGTGAAACCAGTCCC CACAGCAGCT 29251 CTGCCACTCT CTGCTTCTTT TCCAAACAGA CCCTATTTCCAGTCACTCCC 29301 CATGGCCAGC CAGTCCAGAT CACTCTCCAG CCAGCTGCCA GCGAACACCA29351 CTGCCTCAGT GCCAGAACCA TCTACACGTT CAGTGTCCCG AAATACAGCA 29401AGTTCTCTAA GCCCACCTGC TTCTTGCTGG AGGTCCCAGG TGGGTATCAA 29451 GTGGTGCAGAAGGAGAAACT TTCCCTCTGG GCCTTGGGAG CTTCGTGACA 29501 CAGTGGTTAA GAACATGAGCCTAGAGATAG ACTCGCCTGG ATTAAAACCA 29551 CACTCATTGT GTGTCTTTGG GCAGCTTACATAATGCCCCG AACCTTGGTT 29601 TGCACAGTCT GCAGGATGGG TTTATTCTTG TGAGGATTAAATAGGGTCAT 29651 GTATGTGAAG CACTCGGCAC AGGTGCAGTT GTAGACAAGA GCCATTGTTG29701 TTTCTCTCAT TGTTATTTTT CCTTCCTTAG AAGCCAACTG GGCTTTCCTG 29751GTGCTGCCAT CGCTTCTGAT ACTGCTGTTA GTAATTGCCG CAGGGGGTGT 29801 GATCTGGAAGACCCTCATGG GGAACCCCTG GTTTCAGCGG GCAAAGATGC 29851 CACGGGCCCT GGTATAGCAAATCTGGGGGT GTGCGGCAGG TGGGGAGGGG 29901 TTGAGAGTAA GGGAGTGGGG CTGGAGCTATGAGTTGTTCA GATAGAATAT 29951 CAAGATGGTC CAGACTCTTG GACCAAAACA TCTATCTTTGTGTCTGAATT 30001 TCCACCATTA GTAATGCATT CATTTAGTCC TGAATAAAAT GGCAAACAGG30051 CCCTGGAGGG AGCAGTGCCT TAAGTTCCTT TGAGATAAAT AACTTCACCT 30101CTGCTAAGGA TGTGTCAGCT GCTGAGAGCA GAGCCCCTGG CCTTGGACCT 30151 CAGGAGAGACACTCAAAAGG GGAGGAGAGG AGGCACCAAA GGGGACATCT 30201 TAAAAGAGTT CCAATTTTTAGTTCACACTT TAACCCAGGA TAAGCTGTGT 30251 CCTGGCTGAC CTTGGAGTTT CTTCCCTGGTCTGCTGGGTC TCTCCCTTAG 30301 AACCTAGGGG CGAGCTGGGG CAGGGGAAGC CCAGGAGGTGATATAGGTCG 30351 GCCCTGTTCA GATGAGGGCT GGCAGGGGCA GCTTGGGCAT ATGCGAGGCT30401 CCGATGGGCA TGGGGGCTTT GAGGATGGAT TCTGAGTGTC CCTGCATCGT 30451GGCAGGGTGG CAAAGGGAGC ATTTCCAAAT TTCCTGGCTC CAGGATCTGT 30501 GGGAGAATCCCACTAACTGT CAGGGTGACA ACCTCGGGTA GACATGTCTG 30551 TGCCCTGCCC CGTGCCCTCAGCCTTCCTGT TAAGAGCACA CCAGCTGGAT 30601 TTGCAACTCC CAGCGCCTGC ACCCAATGGGCTTTCTCTGG CCTCTGGAGC 30651 CCACATTGCC CCTGCATGTG GCAGGCTGCA AGTGTCACAGCCACCAGCTC 30701 TTCCATTCCT CAACAATGAC TGTGGGTAAA TAGCCCAGGA GCGTCCCCCT30751 CCTGGGATGG TTCTGAGGTG CGTGTGCCCA GTGGCTCCCT GAGTTGCCAG 30801CAGGATTAAG TGCCAGTAGC CCTAGTGGTC AGCTGCTTGA TAACACCCTG 30851 CTTCCTGGCTGCTCCCCCAG TCCCATCTGG TGTGTTCTGG GATCATCTCC 30901 CAAAGAAACT GCTTACACTTGAAGCCTTGT CTGAGGTCTG TTTCTAGGGG 30951 AATTCAGATG ACGATAATTA TGCTTCAGGAAAGCCTPAAT TTTCTGCTTT 31001 TCTCTCCCCT ACCCAAATCA GGACTTTTCT GGACACACACACCCTGTGGC 31051 AACCTTTCAG CCCAGCAGAC CAGAGTCCGT GAATGACTTG TTCCTCTGTC31101 CCCAAAAGGA ACTGACCAGA GGGGTCAGGC CGACGCCTCG AGTCAGGGCC 31151CCAGCCACCC AACAGACAAG ATGGAAGAAG GACCTTGCAG AGGACGAAGA 31201 GGAGGAGGATGAGGAGGACA CAGAAGATGG CGTCAGCTTC CAGCCCTACA 31251 TTGAACCACC TTCTTTCCTGGGGCAAGAGC ACCAGGCTCC AGGGCACTCG 31301 GAGGCTGGTG GGGTGGACTC AGGGAGGCCCAGGGCTCCTC TGGTCCCAAG 31351 CGAAGGCTCC TCTGCTTGGG ATTCTTCAGA CAGAAGCTGGGCCAGCACTG 31401 TGGACTCCTC CTGGGACAGG GCTGGGTCCT CTGGCTATTT GGCTGAGAAG31451 GGGCCAGGCC AAGGGCCGGG TGGGGATGGG CACCAAGAAT CTCTCCCACC 31501ACCTGAATTC TCCAAGGACT CGGGTTTCCT GGAAGAGCTC CCAGAAGATA 31551 ACCTCTCCTCCTGGGCCACC TGGGGCACCT TACCACCGGA GCCGAATCTG 31601 GTCCCTGGGG GACCCCCAGTTTCTCTTCAG ACACTGACCT TCTGCTGGGA 31651 AAGCAGCCCT GAGGAGGAAG AGGAGGCGAGGGAATCAGAA ATTGAGGACA 31701 GCGATGCGGG CAGCTGGGGG GCTGAGAGCA CCCAGAGGACCGAGGACAGG 31751 GGCCGGACAT TGGGGCATTA CATGGCCAGG TGAGCTGTCC CCCGACATCC31801 CACCGAATCT GATGCTGCTG CTGCCTTTGC AAGGACTACT GGGCTTCCCA 31851AGAAACTCAA GAGCCTCCGT ACCTCCCCTG GGCGGCGGAG GGGCATTGCA 31901 CTTCCGGGAAGCCCACCTAG CGGCTGTTTG CCTGTCGGGC TGAGCAATAA 31951 GATGCCCCTC CCTCCTGTGACCCGCCCTCT TTAGGCTGAG CTATAAGAGG 32001 GGTGGACACA GGGTGGGCTG AGGTCAGAGGTTGGTGGGGT GTCATCACCC 32051 CCATTGTCCC TAGGGTGACA GGCCAGGGGG AAAAATTATCCCCGGACAAC 32101 ATGAAACAGG TGAGGTCAGG TCACTGCGGA CATCAAGGGC GGACACCACC32151 AAGGGGCCCT CTGGAACTTG AGACCACTGG AGGCACACCT GCTATACCTC 32201ATGCCTTTCC CAGCAGCCAC TGAACTCCCC CATCCCAGGG CTCAGCCTCC 32251 TGATTCATGGGTCCCCTAGT TAGGCCCAGA TAAAAATCCA GTTGGCTGAG 32301 GGTTTTGGAT GGGAAGGGAAGGGTGGCTGT CCTCAAATCC TGGTCTTTGG 32351 AGTCATGGCA CTGTACGGTT TTAGTGTCAGACAGACCGGG GTTCAAATCC 32401 CAGCTCTGCT CTTCACTGGT TGTATGATCT TGGGGAAGACATCTTCCTTC 32451 TCTGCCTCGG CTTCCTCATC TGCAGCTACG CCTGGGTGTG GTGAGGGTTC32501 TAGGGGATCT CAGATGTGTG TAGCACGGAG CCTGCTGTGT CCTGGGTGCT 32551CTCTACGTGG TGGCCGGTAG AATTCTCCAT CTATCCAGGC TCCAGGAGAC 32601 CCCTGGGCATCTCCCACCTG TGGCCCCTAA ACCCAGAGTG ACTGAGAGCA 32651 CTTACCATTC AGCTTGTCTCATCCCCAGTC TACCTCCTTC CTTCTACCCT 32701 CACTGCCTCC CAGTCAGGAG AGTGAGCTCTCAGAAGCCAG AGCCCCACCC 32751 AAGGGGACCC TGGTCTCTCC GCCTTCACCT AGCAATGGGAACCCTGCTTC 32801 CCAGGGGAGG AACCAACTGC TCCACCTTCT AGGGACCCAG TTTGTTGGAG32851 TAGGACACTA ACATGGCAGG AATCGGACTT CTGGGCCTGT AATCCCAGTT 32901TGGATGGCAC GTTAGACTCT TGGTTGACCG TTGTGGTCCT TAGAAGTCCC 32951 ATTCTCCCTTCCAGTTATGA GAAACCAATG CCTTCTAGAT TCAGGTGACT 33001 ATCCTTACCT GGGGGTGCTGATGCATCCTC AGTTAACCTA CACCCACCTG 33051 AATATAGATG AGCGTAGCTG AGTTTTCACCCGTAGGACCG AAGTGTTTTG 33101 TGGTGGAGTA TCTGAACAAC CTTGGCTCTG TGGCCATTCAACCTGCCAGG 33151 ACTAACATTT CTGGATTTGT GAAGAAGGGA TCTTCAAAGC CATTGAACCC33201 ACAGAGCTGT GTTGCTTTAA AGCCACCACA AGGGTACAGC ATTAAATGGC 33251AGAACTGGAA AAGCTTCTTA GGGCATCTCA TCCAGGGATT CTCAAACCAT 33301 GTCCCCCAGAGGCCTTGGGC TGCAGTTGCA GGGGGCGCCA TGGGGCTATA 33351 GGAGCCTCCC ACTTTCACCAGAGCAGCCTC ACTGTGCCCT GATTCACACA 33401 CTGTGGCTTT CCACGTGAGG TTTTGTTTAGAGGGATCCAC TACTCAAGAA 33451 AAAGTTAGCA AACCACTCCT TTTGTTGCAA AGGAGCTGAGGTCAAGGGTG 33501 GCAAAGGCAC TTGTCCAAGG TCGCCCAGCA GTGCTGCTCT GATGACTTGT33551 GCACATCCCC AAGGGTAAGA GCTTCGATCT CTGCACAGCC GGGCCAACCT 33601CTGACCCCTT GTCCATGTCA GTAAAATATG AAGGTCACAG CCAGGATTTC 33651 TAAGGGTCAGGAGGCCTTCA CCGCTGCTGG GGCACACACA CACACATGCA 33701 TACACACATA CGACACACACCTGTGTCTCC CCAGGGGTTT TCCCTGCAGT 33751 GAGGCTTGTC CAGATGATTG AGCCCAGGAGAGGAAGAACA AACAAACTAC 33801 GGAGCTGGGG AGGGCTGTGG CTTGGGGCCA GCTCCCAGGGAAATTCCCAG 33851 ACCTGTACCG ATGTTCTCTC TGGCACCAGC CGAGCTGCTT CGTGGAGGTA33901 ACTTCAAAAA AGTAAAAGCT ATCATCAGCA TCATCTTAGA CTTGTATGAA 33951ATAACCACTC CGTTTCTATT CTTAAACCTT ACCATTTTTG TTTTGTTTTG 34001 TTTTTTTGAGTCGGAGTTTT GTTCTTGTTG CCTAGGCTGG AGTGCAGTGG 34051 TGCGATCTCG GCTCACTGCAACCTCCACCT CCCGGGTTCA AGTGATTCTC 34101 CTGCCTCAGC CTCCCAAGTA GCTGGGATTACAGGCACCCG CCACCACACC 34151 TGGCTAATTT TTTTGTATTT TTAGTAGAGA TGGGGTTTCACCATGTTGGC 34201 CAGGCTGGTC TCGAACTCCT GACCTCAGGT GATCCGCCCG CCTCGGCCTC34251 CCAAAGTGCT GGGATTACAG GCGTGAGCCA CCGCGCCCAG CCAAACCTTA 34301CTATTTTTTT AAAGAATTTT TTCCAGAGTT TAATTTCTGA CATAGCTTAA 34351 GTTTTCCAGTAACTCTAAAC TCCATCTCCT TTATCGTCAT TAAGTCATTC 34401 ACAAAAAGCC AGGAGAAGCATTTGGAAAGG GCATGATAAT CAGTATAATA

[0060] Table 5 presents a correlation between the genomic sequence shownin Table 4 and the location of the corresponding regions of the cDNAsequence shown in Table 1. TABLE 5 Region in Genomic SequenceCorresponding Region Sequence Attribute Length in cDNA sequence   1-20015′ sequence 2001 — 2002-2059 Exon #1 58  1-58 2060-8326 Intron #1 6267 —8327-8450 Exon #2 124  59-182 8251-19513 Intron #2 11263 — 19514-19698Exon #3 185 183-367 19699-27229 Intron #3 7531 — 27230-27372 Exon #4 143368-510 27373-29279 Intron #4 1907 — 29280-29439 Exon #5 160 511-67029440-29730 Intron #5 291 — 29731-29861 Exon #6 131 671-801 29862-31021Intron #6 1160 — 31022-31780 Exon #7 759  802-1560 31781-31783 Stop 31561-1563 31784-34450 3′ sequence 2667 —

[0061] Several sequence polymorphisms have been identified in thesequence shown in Table 4. These are summarized in the Table 6: TABLE 6SNP Position SNP Changes variation 30962 allele = “A” allele = “G”variation 30655 allele = “A” allele = “G” variation 28744 allele = “A”allele = “G” variation 28448 allele = “C” allele = “T” variation  9426allele = “A” allele = “G” variation  9162 allele = “A” allele = “G”variation  8811 allele = “C” allele = “T”

[0062] A CRF2-encoding nucleic acid is also present in the genomicnucleic acid sequence shown in Table 7: TABLE 7AGGAAGGAAGGAAGGAAGGAAGGAAGGAAGGAAAGAAAGAAAGAAAGAAAGAAAGAAAGA (SEQ IDNO:22) AAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAGAAAGGAAGGAAGGAAGGAGAAAAGAAAGTCAACAGTCAACATTTCAGAGATCCCAAGATACCAACACTGACCGTGCCTGCTGCTCTTCCATCCTCCTCCACCCTGCGCCTTTGAGGTGGAATTGCGTCCTCTGTGAGCAGGGCTTTGTTAAGAGATCCTAATTAAGGCCAGGCACAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGGCTGAGGTCACCTGAGGTCAGGAGTTCAAGACCAGCCTGCCCAACATGGTGAAACCCCATCTCTACAAAAATTAGCTGAGCATGATGGCAGGTGCCTGTAATCCCAACTACTTGGGAGGCTGAAGTGAGAAAATAGCTTGAACCCAGGAGGCGGGGTTGCAGTGAGCCAAGATCACACTATTGCATTCCAGCCTGGGCGACAGAGCTTTTGTCTAAAAAAAAAAAAAGAAAAAAAATCCTGATTAAGCAGAAGCCTTGATGCTAGTCCCAGAAGCATCCTGAAATTTCCAAAAGAAATTTCCCCCGCGGTTAAACTCAGAGCAACTTTTGGACCCACCAAGCTCTGTGAAAATCATTTTCTCTTCCAAAAACTGATGGGACCAAAGCTGATCCCAGTTTCAAATAATTATCAAAAAATTGGAAACGAAATATGATCAGAAAAGAAGAAAGTTGAAAAAGAAAATCCTCATCACCCAAAGACAACAACCATTAATATTTTGGTAATTATTATTCCAAATATCTTTCTATGCATACAGACAGACTGACACACACACACACACACACACACACACACACACACACACTTTTTTTTTTTTTTTGAAACTGAGTTTCACTCTGTCGCCCAGGCTGGAGTGCAGTGGCGCGATCTCGGCTCACTGCAACCTCCGCCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCCTGATAGCTGGGATTACAGGTGAATGCCACCACGCCCGGCTGATTTTCTGTATTTTTAGTAGAGACGGGGTTTCACCATGTTGGCCAGGCTTGTCTCCAACTCCTGACCTCAGGCGATCCACCCGCCTCACCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCTACACACACACTTTTTTAATGGGCCTATGTTTTAGCACTCGCTTTTCTGTTTCTCAGTGTGTTGCAAACACCTCGGTGTCGATACACACCATTCGGCAACGTCCTCCTAAAGGGCCGCATAATATTGCGCGTCGTGGCGTGTGCCTTACTGGGAAGCTACTGCTGTCCAGGTGAACACCACAGCCTTCGGGGTCAGAAAGACAGCTTTCCCCAGAACAAGCACCTGAAGCTCTGGGGCCTGCCGCTCCCCGGGAGAGAAGTACGTGGAGAAGGGCAGCACGGATCCGCCGGGATCCCCGGGGGCATTAAAGGGAATCGCGTGTGTAAGGCGCGGAGCTCAGCATCCGGCTCAGAAACGCGCTCGGATCCCGCCAATGGCATTGAGGCCGCGTAGCCAAACCGGCCTTGAACTCTCCCTAATCCTGCCAAAATGGCCCGTCCTGGAGCACTGGACTGGCCGTGGGTTATTGATCATCAGCCGGTTTCTTCCCCTCCCCTGCCCTTCCCCCGTGCACGGATTTACTGATTTTTTTTTCCGGGAATTGAGTAAAACAAAACTAAGTGCAGATGAAGCAGAGGTACGGGCGAGTTTCGAGCGCGGGGACCGGCGCGCTCCCCCCCCCCCCTCCCCCCGCGGCGGGGCTGTCCCCAGGGACCTTCTCAGTGAATCCTAGGCGGCAGGGACGGGCCCGCGGCTCTGCGGGCCATTGGCTGCCGACTGCGTCACCTGCCCGCGGTGGGCTAGGAGACGGGAGGCGGGAGGCGGGAGGCGGGGACCTGGGTCCGGGCGGGGACGCCGCGGCAGGAAGGCCATGGCGGGGCCCGAGCGCTGGGGCCCCCTGCTCCTGTGCCTGCTGCAGGCCGCTCCAGGTAAGGGCGCGGGGCCGCGGGAGGGAGGGGGAAGAGGGCTCCCCGGGCCGGGCCGCGCCTACCCTCGGACCCGGAGCTCCTGGGACAGGCACGGGGTCCGCAGCCACCCGAGCCGGGTGCGAATCGGCCCTGCCTACGCGCCCCCAGTTTGCTTCTTCCCAGGACTGAACAGAACCGGGTCTTTGATATTCCTCTCCCGCAGGAAACGAATCCAGTTTCCTAATGCTTCCAGCTTCAGGAGAACTGGAGAAAAAAGACAGCGGCAGTTTGATACTGCATATTTTTTAATAAAGTGCTTTTTAATGTTTCCTAAAGAAAGCACTGATCCCTGCGTGAAAACCACACTTGACCCTAAAGTGTGGACAGCAGGGAAAGTGGGACCGATTGATGTCCCTTCCCGTTCCTGCCAGGCCTCTGGTGGGACGGAGCTCTGGTCGCCTGTGCCCTGCTTTCTAACAAGACGGCTTTCTTTTGGTGGTGGTTGTTGTTTTGTTGTTGTTTTGTTGTTGTTGTTGTTGTTGTTGTTTTCCCACCTCTACTGATGAGTAAGGTGTCAGGTACAAAATTCCTCGCCGTAGGACCCAACCACCAAACCTCACCGCCCACGACTCCAACCGAAGCAGGGAAGAGAAGGTCCAGAAATCGCCCCCAGGATATTTTCCTAGTCTTGGACTCACAGTTTAAAGAGCTGTAAAGGTCCCTGGGCATAATCCAATCATCATAAAAGCCTATATTTATTCAGCAACTTCTTTGTGCCAGGCACCGCATTATTCTGGAAGCCTCACGACCCAGCCATCCTAGGAGGTAGATATTATTTTTACTTTTCCGATGGGAAAACTGAGGCTCAGAGCAATTCAGGGAATTCCTCAAGAAGGACGGCAGAGGTGAGGCACACAGAAGAGAGAAGAGGGGCTAAAGCAAGCCTGGCTAGCTTTTGCCTCCAGGGTAGGCACGTGGGACAGGCTGTCCATCCACTGGGTCACTAGGCCAGCCAGGGATGCTCCAGCCCCCAGTGCCCACAGCAGCGTTCTCTGTGGCTQATGAGGGACCGTGTACCTGTGTGTGGAGGGAGGGTGGGGTCTTCTGTTCCCCTTTCACTGTCAAGCCCAGACCTTCTTGTACTTTCACCTGATAAGTATTTAATATACACAACACTAACTATGGTGTGATGATTTAGGAGTAAGTACAGCCAGATCTAAGTTCAAATACTGGCTCCCACACAAACTGACTGTGTAGCCTCAGGCAAGTTAGTTAGCATCTGTCTCTGAGCCTAGCGCCCTTTCCATGGAAGCAGAATGAATGACACCTACCCCATAGGGTGGTCTGTCCCAAGGGTGATTGAGGTTTTACATGTAAAGAGCCAAACTAGTGCCTGGCATCCTTTGAAGGCTTCATAGAGGAAAGTTGCTCTAGCTGCTGTTTTTCTCATGTGACCTAGCTCGAATCTGGGGACTGTCCTGCCCATAGGATACCTTACAAGTGGCTTGCAGACAGCCTGGTCTCCTGCTGGTCACCCGTTAGGAAGTCCAGAAGCTGGGAGTAGTAATAGCACTAGCCTCGTGGTGATACAGTCCCAGCTAGAGGACACAGGATGAGGTGGAAGCAGGCACCCACTTTTGGGTCTAAAAGGTGATGGGTAGGCAGCCGAGGCTGGGGACAGCCATCCACAGAACTGGACCCTCCCTCCCTGATGCCATTTTGCAACCCGTATGGATTTCCATCATGGCACATGGGACACTTCAGGACCCTGAATTCTCCATGGGACCATGAGCTCCTATAGGGCAGGAATGAAGTTGTGTTCTTCTTTGAAACCCCTGGCACACCGTGGTCAACAGATCTTGTTTGACTCGTAGTGGTCAATAGATGGAATAGTTGGAATCATAAACCTCAATAGACCCCATGAGAACCTAGAAGACAAAGTACAGTCAAGAGCTCGGACTTTGGAGTTGGCTAGGCCTGGACTGAATCTGATTCTACAACTTAATAGCTGAGAGGGCCTTGGTTTTCCCATCTGTAAAGATTATAATTATTATAATGAATACCTACCTCCTAGGGATGTAATGAGGATTAAAAGAGAAAGTGCAGGTAAACTGTTTAACACAGAACCTGGCTCATAGAACACAATACACATTAGCTGCTATTATTATTATTATTATTTTATTTATTTATTTTGAGACAGAGTCTCACTCTGTCACCCAGGCTGGAGTGCAGTGGCGCAATCTCGGCTCACTGCAACCTCCACCTATCGGGTTCAAGCAATTCTCGTGTCTCAGCCTCCCAAGTAGCTGAGATGACAGGCGTGTGCCACCATGCCCAACTAATTTTTGTATTTTTAGAAGAGACGTGGTTTCACCATGTTGGCCAGGCTGGTCTCAAACTCCTGACCTCAGGTGATTTGCCTACCTCTGCCTCCCAAAATGCTGGGATCACAGGGGTGAGTTACCATGCCCGGCCTTAGCTGCTATTATTATCATCATCGTTATCATCATCATCATCACCTCGTAGATATGTCAAGGAAGATTCCCTGGAGGAAGTGACATTTGAATCAAGTATTTCAAAGACTAGATGGTGAATACCAGGCAGTCAAAGACACCTGGGTTTAAAAACATCCAGAAGAATGCAGTGGCTTGGCAACATCGAGCAGGAAGATTGCCTGATGAGCCTGTAGGGTAGCTGTTGGGGAGAGAGCAGCAAGACGGCCTGGCCAGGCCAGGCCAGGCCACGTCAGGCAGGGCCTCACAAACCTCAATAACAAATGTGGACTTTATTCTGAGGCCAAGGAAAGGGCATGAAACTGGGGAGTGGTGTAATCAGATGCGTATTTCAGAAGATGAAGATTAACAGTGAGAAGGAAAATGTGCCACAGAGGGGAATAGAGGTCAGTTAAAGGGAGTCAGGGAAAGTGTCCTCGAGACAGTGACATCAAAGGAATGTGAAAACAGCAAAGGAGTGAGCCAGGTGGATATCCAGGGGCAGAACTGTTAAGGCAGAGGCAACAGCATGAGGGAACAGCGTGTGCAAAGGCCTGGAGTTGGGAGTGTGGCTGGGGTGCTCCAGGAAGGGCAAAAAGTCCTGTGTGGATGGAGATATGGGAGCAAGGGAGGAGTGGTGGGTCAGATTGGGTAGGGCCTTGGTGGTGATTGTAAAGACTCTGGAGTTTAGACCAGGCACAGTGGCTCAGGCCTGTAATCCCAGCACTTTGAGAGGCCAAGGTGGGCGGATCACCTGAGGTCAGGAGTTCGAGACCAGCCTAGCCAACATGGTGAAACCTCGTCTCAACTAAAAATACCCAAATTAACCAGGTGTGGTGGCACAAACCTGTAATCCCAGCTACTCTGGAGGCTGAGGCAGGAGAATCGCTTGAACCCGGAAGGTGGAGGTTGCAGTGAGCTGAGATTGTGCCACTGTACTCCAGCCTGGGTGGCAGCATAAGACTCTGCCTCAAAATAAAATAAAAATAATAAAGACTTTTGAGTTTCCCTGGAGTGAGAGGAAAGCCTTAGAGGGCTTTAGCAGGAGATGAACATGATCTGATTTTCATTTTTAATCCTTCCTGCTATGTGGAGAATGGACTGAAGGCAAGGTGTTTTGTATATTTGTCTGTTTCGTAGAGACAGGGTCTTGCTCTGTTGGCCAGACTGAAGTGCAGTGGCACAATCACGGCAGCCTTGAACTCCTGGGCTCAGGCGAAACTCCCACCTCAGCCTCCTTACTCTCACCATTGTGCCCTGCTAATTTTTTAAAAAATTTATTTTGTAGAGATGTGGTCTCACTATGTTGCCTAGGCAAGTCTTAAATTCCTGGTCTCAAATGATTCTCCTGCCTCGATGTCCCAAAGTGCTGGGATTACAGGTGTCAGCTGCCATGCCCGACCTGTATTTTTTTTTTTAATGGGGAAAAAGCCTTTTAATAGTATGAGGTGTTTTCTGGTGTTTCTACCATAAAGCTCTTCTGTAAATCAAAATGAGAATGTAATTATTGATAGAGCAATGACCTTAGACTACAGTGCAGACTTTTCATCTTACATTTGGGCTCATGAATTTTAGTATAACTGATTATGACAGTGTTTTTTACATAGTTATGATCTAGAGCAGAACTGAAAACAAAATAACACATACTCTACATCAATATATTCGTTCAGTAATATCTGGGCTTGGATGAACCTGCAGAAGTAGGTAAAGCTGTCAGATATTTTCTTAAACCAACAGAAAAGAAATGTATATGACAGATGTTGTGTTTACTTACTTATTTATTTATTTATTTATTTATTTGAGATGGAGTCTCACTGTGTCACCAGGCTGGAGTACAGTGGTGTGATCTCTGCTCACTGCAACCTCCACCTCCCGGATTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGATTACAGGCGTGCACCACCACGCCTGGCTAATTTTTGTGTTTTTAGTAGAGACAGGGTTTCACCATGTTGGTCAGGCTGGTCTCGAACTCCTGACCTCGGGATCTGCCCACATCAGCCTCCCAAAGTACTGGGATTACAGGCATGAACCACCACGCCCAGCCTGTATTTATTTTTTTACCACTATGGAGTCCAATATGAAATTCTCACAACTATGCATATACATTATTAACATGTAAGCACACCTAGGTATAAATATGCACATAGTCCATTAATTACATCAGGGGAATTAAAAACATACTTTCAAGTTAAAATGAATTTTCAGGAAAAAAACTGCATTCACAAATCTGAAATGTGAATACAAAAATGAAATTGTGAAATAAATAATGAATATAGGTGTCACCTAAACTTCCATAGTAACATGCCTCCAAATGTGGATTTAGTGATCATCCACCTTGGGACAAGGGCTTTTGAGAGCCTCCAGCTAAATTAGGGTTCCAGTAGCAGAGTGGCTGGCAAGCCTGCCCTAATGAATAATGCCAGCGAGCTGGGCGTGGGTACTTACAGTGTGCCCTTCATGGAATACTTTTTTTTTTTTTTTTGGAATGGAGTCTCGCCCTGTTGCCCAGGCTGGAATGCAGTGGCACAATCTCAGCTCACTGCAACCTCGTCCTCCTGGGTTCAAGCAATTCTCGTGCCTCAGCCTCCCAGGTAGCTGAGACTACAGCCCTGTGCCATCATGTTCTGCTAATTTTTGCATTTTTAGTAGAGACGAGGTTTCACCAAGTTGGCCAAGACTGGTCTTGAATTCCTGACCTCAGGTGATCTGCCCACCTTGACCTCCCAAAGTGCTGGGATTACAGGCTTGAGCCACTGCGCCCGGCCCATGAAATACTTCTTACCTGGCGGACAGCCTAATAGCCTAGCTGTCTAACCCATGGCTGGGGGTCCTTCACACTTGTTTATACTGGCAGACGTCCCTGTGACTCTTGTCTGATCCATGTCCAAGTTTATGCCTGTCTGACCATTGCTCTGGCGCTGGGAGCCAGACTGTGTTCCCAGCAACCCAGGGAAAACCAGGCCTGGGCTGGGCCTGGGTTCCTGAGATGGAAGGTGCAAATTCAGTACACCACCTCAATGCAAAACAAGTTCAAAGGCTTATTACTTACAGATCCTGAGCAGGGAAGGTGCAATGAGTAGGGAGGGTCATCCTCCATCCTGGGCTACATGAAGCGGGAATGAAGAGTCAGGCAAAAAGAAAGTGAGAGCTTGTGGCAATGAGAAGTATATTATGTAAGGGACTAGGGTGTGGGTCAGGTTAAGTTTGAGGGCAAATGCTTGAATGATCCCTTTAAAGGAATGGGTGGGAAGTGGGGAGCCCAGTTTGCCGGGAGGGAGAGATGCCTCGAAGTTCTTATCTCTGGCCACTGGCTTGGACCATCTGAGTGTGGCATCTACTTCTAATGCCTAGGCAGCAACCTTTGCTGTGTCATCTCCCTTACACAAGGTTGGAAGCAAGGAGACCGGTCAGGAAGCCTTTGGTGTAACCCATGTTATTGTAATATTCATTCATTTACTCAACAGATGTTTATTGTGCACCTACTATGTGCTGAGGCCATGGCAGGCAGGCTCTGGGGATGTGGCTGAGAACAGGACAGAGCCCCTGGTCCTTGATATCCTCAAGGATGCTCCCTCCTGGAGGCCATTAGGTTCCTGTTCCATGGTGTTCTGCTGGAACCCTCCGGTCCCAGAGTGTGCAGGAGCCTCCCCTCCTGGCAAAGGGTCTTCTCTCATGGCACAAGGGCTGCAGTACAGCCAGTCAGTGGCTCCTGGTTCCTCAAACTCAGTGAGCACTTGCCTGCCCTTCGTGCTGCCCCTCAGCTTGGGATGGCCTGAGTCAAGACCAGCCAGGAGCTCCAGGCTTCATGACCCCTTTCTTTCCCCCAGGGAGGCCCCGTCTGGCCCCTCCCCAGAATGTGACGCTGCTCTCCCAGAACTTCAGCGTGTACCTGACATGGCTCCCAGGGCTTGGCAACCCCCAGGATGTGACCTATTTTGTGGCCTATCAGAGGTAGAGGGGACTCTCTCGGCTGGTGGATGGGAAGACTGAGGGGGTGGGTGGGGGCTGGAGGGGCTTCTCTGGGACAGCTGCACCCAGTGTGGGCAGCACTGGCTAGCTCTCTGGGCCCTACGGGAGATGGCATGTGGCCGGCATTTGGAGAGGGGCTTTTGATAAAGGTCTGGAGGTGGGGAAGATGTTGAATGAAGAGCAGTGTACAGGTGACCAGTCTGCCGGGGCGGGGGTAAGTCTTTGAGGAAAGTTGGTGTGGGGCATGGATGTAGCTGTGGGGGCCAGAGGATGAAATTCTCAAGTGGCTGGATGAGGTGCTTGGAGCTGTCCCAGCTGATCAGTGAGGCAACTAGGTACACGGCAGAGGAGCTGTTACCTGGGCAATTAGGCATCCCTCAATGATCACACTTTTTTTCTCTTTTTTTTTTTTTTTTGAGACAGAGTCTTGGTCTGTCACCCAAGCTGGAGTGCAGTGGCTTGATCTCGGCTCACTGCAACCTCCACCTCCTGGGTTCAAGTGATTCTCCTGCCTCAGCCTCCAGAGTAGCTGGGATTACAGGCATATGCCACCACATCTGGCTAATTTTTGTATTTTTAATACAGACGAGGTTTCTCCATGTTGCCCACGCTGGTCTCGAACTCCTGAGCTCAGGTGATCCACCCACCTCAGCCTCCCAAAGTGTTGGGATTACAGGCGTAAGCCACCGCGCTTGGCCAAATGGTCACACTTTTCCCGATGGGATCATTCTCAATTTGGAAGCCCAGGCAGCCACAGCGAATCCAGAGAAATCTGACAATGGAAGCAGATCCACCATCTTCGAACATAGATGGGAATCGTTCAGAGTTCTTTAGCAGGACAGTGAGATGATAGAAGCAGAAGCTCGGGAGGATTCACCTGGAGTTGGTGAGGAGGGGAAAGCAGGAAGAGGAGGGGACCACCGTGTCCTCAGGACCCGTCCTGTGCCAGGCCAAGTGCTAAGGGCCCTACGTGAATATTTCACTTCCTTCTCCCAATGTGACCAGGCAGGCTCTGTGTTTTCCCCATTCTAGAGGTGAGGGGATTGAGCTCAGAGGGTGCTGTGTCTTGTCTGAGGAAGGACGTCATGGAGCCAGAAGGGGAACTCGGGTCCGACTCCAACATTTGTGCCCTTCCTGTTGCATCACGTCATCCTTCCATGTGTGGAATCCACATGTGAGTGATGGGAGCCTGGCTTGAGCAGGGACAGACTGCAAGAGAGCTTTCAAAAGCAAGAGCGTTATCAGGTGCCAGAAAACACCTAATATTTACTGTGTGGCTGGCACTGTGTCAACACATGTAATGAACTTAATCTCACAGCAGCTCTCTGAGGACAAGTTCAGTACQCCTCTTTACAGAGGAGGAGACTGAAGCACCAAGGGTGCATGTTGCTCAAAGTCACACAGCTGGGCGTAGTATGGCTGGAATAAATTTATTAAGGAGTTGAAAGTCTATCCTCTAGGACCAAGCATGGTGGCTTACATCTGTAATCCCAGCACTTTGGGAGGCCGAGGTGGGTGGGGAGATTGCTTGAGTCCAAGAGTTCGAGACCAGCCTGGGTAACATGGTGAAACCCTGTCTCTACAAAAAAAAAAAATACAAAAAATTAGTGAAGTGTAGTAGCATGTGCCTGTGTTCCCAGCTACTTGGGAGGCTGAGGTGGGGAGGATCACTTGAGCCCAGGAGATGGAGGTTGCAGTGAGCTGAGATCACACCACTGCACTCCAACCTGAACAACAGAGCAAGATCCTAAAAAGAAAGAAAATCTATCCTCTGAACTTCTATGATATTTTTCATGTCTTTTATACATTAGAATGGTGATATTCTAATTATATAATTTTTTTCATTTGTTAGTTGGAATTATTTTATAAAGAGATGTATCCTCTCATCTGGTATTTGATATCCAGTCATACTATTCAAATAGGCAAGAGAGGATAAATGCTTAATTTTTTTCCTTTATCAATTTTCAAGATAATGAATTGGTTCCTTATCATCTCCCAAAGGTGATTGCTAGTTTATTATTATCATTATGAACTCAGGCATTTAAACACATTTGGTGGTTTCAGTCTATTGCGACGTACTCTGCTCATTGAAGCTTGAATTGCCTCATCTCTGTCCAGTGGGAGTCTCATCAAGTTTGCTCCTGAGTCCTTTTAACTTGACCCTAGTGGTCAAGTTAAATCTTTCCAGATTTAACAGATACCTTTCCAGCTGTCCATTACGACAAGATGTTCCAGGTCCCTCTGGTACAATTCCTGACCTAAAACCTGCAGTCAGCCATTTCTCCATTTAGTAAGAAATGGTTATAAAGACTATAATCTGCATGCTAGCTATGCTGATCACTACTTAGCTATTGCTTTTGGTGTTTTCAGTGAACAGAGTGATGTGTGTATACCACATAGACACACACATGTACATACTTTTTTTTTTTAGACAGAGCTTCACTCTGTCACCCAGGCCAGAGTGCAGTGGCATGATCTCGGCTCACTGCAACCTCCACCTCCTGGGTTCAAGAGATTATCCTGCCTCAGCCTACTAAGTAGTTGGGATTACAGGCGCCCACCACCATACCCGGCTAATTTTTGTATTTTTAGTAGAGACGGGGTTTCACCATGTTGGCCAGGCTGGTGTCGAACTCCTGACCTCAAGTGATCTGCCCCCCTCGGCCTCCCAAAATGCTGGGATTACAGGCATGAGCCATCGCACCCAGCCTACATGTACATAATTTTTAAGATAAAATGCCTAATGAGTTATACGGGTGCTTCCCATCTAAATTTAGTTCCTTAGGATTTTTACCTGACTTCTATGGTACATCTATATTTTCTTTCTTTCACACTGAGAATCCTGTTTCTCAAGGACAGGGGACATGATAGAACTAGAATGACCCATAATTACTCATTTTCTTTATCCCAAAACATACATACTTGCCTCTTAATAGTTTCTTGCTCTTTTCGCCCAAAGGGTTTGTGATGGTCAATATTAGGTGTCAACTTAATTGGGTTGAAGGATGCCTAGATGGCTGTTAAAGTTTTGTTTCTGGGGGTGTCTGTGAGGGTGTTGCCAGAGGAGACTGACATTTGAGTCAGTGGACTGGGAATGGAAGACTCGTCCTCACTCAGTGTGGGTGGGCACAACCCAACTGGCTGCCAGGCTGGCTGGAAAGCAGGTGGCAGATGGTGGGATAGCTTCGCTTGCTGGGTCTTCCAGCTTCCTTCTTTCTCCCGTGCGGGATGCTTCCTTCTGCTCCTCCTGCCCTTGAACATCACACTCCGGGTTTTTTGGCCTTTAGACTCTTGGACTTAAGTTAGTGGTTTGCTGGGGGCTCTCGGATCTTTGGTCACAGACTGAAGGCTGCACTTTCAGCTTCCCTGGTTTTGAGGGTTTCAGATTCGGACTGAGTCACTATGGCTTCTTTCTTTCCCACCTTGCTGACGGCCTATCGTGGGACTTCGCCTTGTGATCGTGTGAGCCAATTCTCCTTAATAAACTCCCTTTCATATATACGTATAACCTATTAGTTCTGTTCCTCTGGAGAACCCTGACTAATAAAGGGTTGTTGCTTTTTCTTTAAAATCTAGTAATTTTATTTGACTGTGTGTTGGTATTGCTCATTCATTCTGAGTTGATATTTTTAGGCACTCAATATTCTCACTTAATACATGGTTCCAAGGCATTTTTATTTTAGGAAGGTTTTCTTAAATTATAGTTTTAGTATTTGTTCTATTCTCTTGTTTTGATTTTCTTCTTTAGGGACTCATATCACTTGTATGTTGGATCTTCTTTTTCTGTGTTCAGTATTTGTCTTTTGGGCACAGAGACTCACACCTATAATTCCAAGACTTTGTGAGGCATAGGTAGGAGGATCGCTTGAGCCCAGGAGTTTGAGACCAGCCTGGGCAACATGGTGAGGCCCTGTCTCAAATTAAAGAAAAAGGAGAGAATACTTGTCTTTTTCTTTCAAATGCCTTTTATCTGTCTGTCTATCTACTATTCTGCTCTCTAAATGAAATAGGTTTCACTCTTGAGTTTTTAAAAAACTGTGTGCTTCCATGTGTGAGATTATTCAACATCTTATTTGTAATCTTTCTCTTGGTTACATTTATTTTTCCTGAAACTCTAGTCTGCTTTTAGCTGACATGTTTGTAGCTAAGAGCGCACATTTCTTATCATAGCTTGCCGTGCTGAATTAATTCCAATTTTCTTTTAAAACCAACATTATTGAGTTAAAATGTATATAGAATAAACTGTTCCCATTTTAAAGTATACAATTTGATGAGTTTTGACAAAAGTGGGCACCCACGTACCCACCACCACAATCAAGATGTAAGACGTTCTCTATCACCCCAGAAAGTTCCCTCATCCACTTTGCATTCAGGCCTCCAGATCTAGGCAACCACAGATCTGCTTTCTGACACTGTGGATTAAACTTTGCCTGTTCCAGAATTTCATATAAATGGATGTGTATAGTATGTACCCTTTCGTGTCTGGCTCCTTTCCCTCAGCATAATGTTTCTGAAATTCACCCACATTGTTACATGTATCAGTAGTTAATTCCTTTTTATTGCTGAGTAGTAATGCCATTGTATGACTATGTATGACATTTGTTAATCCATTTTCCCGTCAGTGGATATTTGGGTTGCTTCCAGTTCTGGGCAGGTATTCATTTGCTAGGGCTGCCATATGCTTGCCCTCTGGCCTCCCAAAATTTGTGTCCTTTTCATATGCAAAATACATTCACCCCCTCCCAACAGCCCCAAAACTCTCTTTTTTTTTTTTTTTTGAAACAGAGTTTTGCTCTTGTTGCCCAAGCTGGAGTGCAATGGTGTGATCTCGGCTCACTGCAACCTCTGCCTCCCGGGTTCAAGAGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGATTACAGGCATGCGCCACCACGCCTGGCTAATTTTTTATATTTTTAGTAGAAATGGGGTTTCACCGTGTTAGCCAGGCTGGTCTTGAACTCCTGACCTCAGGTGATCCGCCTGCCTTGGCCTCCCAAAGGGCTGGGATTACAGGCATGAGCTACTGCACCTGGCTAGCCCCAAAACTCTTAACCCATTTCAGCATCTACTCTAAGTCCAAAGTCTCATCTAAATCAGGTATGGGTGTGACTGGAGGTGTTACTCATCCTGAGGCCAAATTCCTCTCCACTTATGAACCTGTGAAACCAGACAGGTTATGTGCTTTGAAAATAAAGTGATGGGACATGCATGGGATAGACTTTCCCATTCCAAAAGAGAAAAATAGGAAAGAAGGAAAGAGTGACAGGTCCCAAGCAAGTCTAAAACCTCGCAGGGCAAATTCCATTAGATTTTAAGTTTCAAGAATAGCCCTCTTTGGCTCAGTGCTCTGCCCTTTGGGCCCACTGGGGCGGCAGCCCTATCCCCTTTGCCCTGGGTGGTGACCCTACCCTCGAGTCACTGGTTAGCAGCAGCCTAGCCTGCTGAAACTAAGGAGGGGACAGTGTTGCCTCCAGGTCTTTGGTGGCAGTGACAACCCTGCTGATCTCTGAATCATCTTCCAGGAAATTTTTCCCTATACTTGAAGGATATTGCGTGTTCACAGCCAAATAGCTCCAGCTCTTGTCCCTTTCTTTAGAATCCCAGAAGTCCAACAGCCTTCCTTCATTCTGTCCCATCTCTGTCCCCTTTAGTCAAAGCTGGAAGTGCCTCTGCTGGTATAATCCCATCAGTATGTCTAATTTCTGCTTAAATGGCTGATTAAGTCTATGAGTTGCACCTCTGATCTCTTTATCAAAAGGTTGTTCTAGCCACAACCTTAGTGTCCTCCCCAGAACATGCTTTCTCATTTTTTTTTTTGCAATGTGGATAGGCTGAAAATTTTCCAAAGCTTCAAGTTCTAGTTCCTTTTGGCTTACCAATTCTTTTCATATATCTCTTCTCTCACATTTTACTATAAGCAGTAAGAAGAAACCAGGTTGTACCTTCAGCACTTTGCTTAGAAATCTCTTCTGCTAAGCATCCAAGTTTATGTCTTTTAAATTATCTTTTTGTTATTTATTTTATATTATCATTTTTGAGATGGCTAGCCAATGATCTTTTAACTTCTAATTTCTGCAAAACACTAGAAGACAATTCAACCAGTTCTTTGCCACTTTATAACAAGGATCACCTTTCCTCCAGTTTCCAATAACACATTCCTCTTTTCCACCTGAGACCTCACCAGAATCACCTTTAATGTCTATATTCCTACCAATAGTCTTTTTAAGGCAATATAGGCTTTCTCTAACATGCACTTCAAACTTCAAGATTCTACCCATTATGCAATTCCAAAGCCACTTCCACATTTTTAGGTATTGATTACCTCAGCACCTCATTTCTGGTGCCCAAATCTGCACTGGTTTGCTAGGGCTGCCATAACAAAGTACGACAGTCTGGGTAAACAACAGAATTTTATTTTCTCAAAATTCTGGAGGTTGGAAGTCCAAGGTCAAGGCGTTGCTAGGTTTAGTTTCTCCTGAAGCCTCTCTCCTTGGCTAGCAGATGGCTGCCTTCTTGCTGTGTCCTCACGTGGCTTTTTCTCTGTGTGTGTTCACTCTGGTATCTCTTCCTCTTCTTACAAGTACACCAGTCCTACTGGATTAGGGCCCCAGCCTTATTACTTCATTTAACCATAATTACCTCTTTAAAGCTCTTATCTCAAAACACAATACCACTGGGGATGAGGTCTTCAACATATGAATTTTGGGGGAACTCAATTCGTCCATAATAGGGCTATTATGAATTAAGCTGCTGTGAACATTCATGTACAAGTCTTTGTGTGGATATGTTTTCATTTCTCTTAGATAAAGATCTAGGAGTATCAGCCTGGGCAACATAGTGAGACCCCATCTTTACAAAAAATTTTCAAAATTAGCCAGGCATGGTGGCGTACACCTGTAGCCCTGCCATCTCAGGAGGCTGAGGTGGGAGGATCCCTTGAGCCCAGGGGTTTTAGACTGCAGTGAACTATGATTGCACCACTGCACCCCAGCCTGGGTGACAGAGTGAGACTCTGTCTCTAAAAAAAAGAGAGAGAGGGGAGGAAGGAAAGAAGAAAGAGAGGGAGGGAAGGAGGGAGGGAGGGAGGGAGAAGAAAAATGGATCTAGGGTTAAGATTTAGGAGATTAGGTAATGAATGTGTACTATTACAGGGAACTGTCGAGCTGTTTCCAAAGTGACTGTACCATTGTTCATTGCCACCAACAATACATGAGAGTTCTAGTTACTCCATGTGCTTGTTACACTTAGTATTATCAGTCTTTTTCATTTTAACCATTCTAGTGAGTATGTAGTAGTATTTTATTATGGCTTTAATTTACAACTCCCTAATGATGAATGATGTTGAACATCTTTTCATGTGCTTATTGGCCATTCATATATCTTTTGTGAAGTGACTATTCAAATATTTTTCCACTTTTTATTAGGTCATTTATTTTCTTATTATTGAGTTATCTATGAATACAAATCCTTTATCAGTGTATGTATTGTGATTTTTTTCCCCAGTGGCTGGCCTTTTCATTTTCGTTAGGCTTTTTTGGTGGGTTTTTTTTTTTTTTTTTGGAAGAGAAAAATATTTTAATTTGATAAAATCCAGTATATCAGGTGTTATAGACTGAATTATACTCTACCCCACAAATTCATATGTTGAAGCCCTAACCTCTAAGTGACTATTTGGAGATGAGCCTTTAAGGAGGTAATTAAAGTAAAATGAGATCATAAGGGTGGGCCCTAATCTAATAGGACTGGTGTCTTTATAAGAAGAGGAAGACACCAAGAGCGCATGCACACAGAAGAACGGCCTTGTGAGGACACAGCAAGATGACGGCCATCTGCAAGCCAAGGAGAGAGGCCTCAGTAGAAACCAAACCTGCTGATGCCTTGATCTTGGACTTCCAGCCTCCAGATTTCTGTTGCTGAAGCCACCCTGCCTGTGGTGTCTTACCATGGCAGCCCTCACAGACTAATATATCAGATTTTTTTCCTTCAACAGTTAACGCTTTTGGTGTCCTAAGCAATATTCGCCTGACCCAGGGTCATGAAGATTTTTCTTCTATGCTTTCTTCTGGAAGTTCTATAATTTTAGCTTTTACATATTTTTTTAACTTTCCTTCTTCTTGCCTTCTGTTTCTTTTAAGGCATCATCTATTGTGTTAATTTGTTCTTGTATTCCTTCTGATTTATTCTTCACTTCTGAAATGAATTTTGCTTTTTAAAAATATATATAATTCTTTTCTGTGTCTGAGTTTTTCTAATTAGGTTTTATGTGGTTTTTTCTTGTCCTGCATCACTTTTTACTGTCTTTTGCCCATTTTGAAGTATCAGGTTCCAGTTTTGATCTGTTCATGGATATGTTTTTGTGACATGTTTCTTCTGGCTTCTTATCATTTATTGCTTAGCTTATTAATTTCTATTCTTTCTTATTTTCTATTATAAGTATTTAAAGCTATATGTTTTCCTCTAAGTATTACTTAGCTGTCTTATACGTTTTCATTTGTGTTATTTGGTGATCATTCACTTTCAGCTATTTATTAATTTCCATTATAATTCTTTCATCTATGGGTTGTTTTAAAAAATATTTTTAAGGCCAGGTGTGGTGACTCACATCTGTAATCACAGCACTTAGGGAGGCTGAGGTGGGAGGATTGCTTGAGGCCAGAAGTTTGAGACCGGCCTAGGCAACAAAGTGAGACCCCCTCTCTACAGAATATTTTTTTAAAATTAGCTGGGCCAGGCGTGGTGGCTCATCCCAGCACCTGTAATACCAGCACTTTGGGAGGCCAAGGCAGATGGATCACCTGAGGTCAGGAGTTCGAGACCACCCTGGGCAACATGGTAAAACCCCATCTCTACTAAAATATAAAAATTAGCCAGGTGTGGTGATAGGTGCCTGTAATCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATTCTTTGAACCCAGGAGGAGGAGTTTGCAGTGAGCCGAGATTGCACCACTGCACTCCAGCCTGGATGACAGAGCGAGACTCTGTCTCAAAAAAAAAAAGAAAAGAAAATTAGCTGGGTGTAGTGGCAGGTACCTGTGGTCCCAGTGACTCAGAGACTGAGGCAGGAGGATCACCTGAGCCCAGGAGTAGAGGCTGCAGTGAGCTATGTTTGTGCCACTGCACTCCAGCCTGTGCAACAGAGCAAGACGCTGTCTCAAAAAATATATATTTTTTTAAATTTTCAAACTTCCTTTAGTTCTCTTTTTGTTATTAACTTTTAACTGAATGTTTTGCAATCAGAAGAAATACTTTATGAGATACCTATTCTTTAAAATTTCTTAAGAATTGCTTTGTGTTAATATTTTGTTAATAGTTCACATGTGGTTCAACCAATTTGTTTAGTTAGTTCTGTATATGTTCATTAGACCAACTTGATAACTGTGTTGTTCTTTATTTATTTATGTATTTATTTTTCTTTGTCTATTCATCAATTGCTGGGTGAGATGTATTAAAATTTCTTGTTGTAAGTGTGGCTGTTCACTTTCTACCTGTAGTTTGTCTGTTTGCTTTATAGAGGGTGAAGTTGTTTAGTAGGCACACATAAGTTAGAATTTTTCTGTCTTCCTGGTGAATGGAATCATTTATCATTATCTAATGTTCTTTTCATCTTTAGTATTGCTTTGGACTTGGAAGTCTGTATTTTGTCTCCTGTTAATATAACTACACTGGTTCCTTTGGTGTGAATATTTGCATAGTATAACATTTTCCATGAAGAAACAAAACAGAGGAATTGGTTCTTTCTCAAAATCTGATCTTTGTGTCAGCCCCCATCTCAGCCTTCTCCATTCATCCTTGGTCACTCCCCAAACCCAGGAGCAATCCTTGATTCTCCTTTTCCCCACATTCTACATCCAATCCGTTAGCAAGTTCTATTAGTTCTATTATTACCTCCAAAATAGATATTGAATCCAGCCCTTTCTCACTGTCTCCACCATCATCCTGTCTCACATCCCTACCATGGCCTCCTTGCTGGTTGACCAGAGTGATCTTGTAAAAACATGTTAGGCCAGGCACGGTGGCTCCTGCCTGTAATCCCAACACTTTGGGAGGCCAAGCGGGTGGGTCACCTGAGGTCAGGAGTTGGAGACCAGCCTGGCCGACATGGTGAAACCCTGTCTCTACTAAAAATACAAAATTAGCCAGGTGTGGTTACGCTGGCCTGTAATCCCATCTACTCGGGAGGCTGAGGCAGGAGAATCACTTGAACCCAGGAGGCGGAGGTTGCAGTGAGCCAAGATCATGCCACTGCACCCCAGCCTGGGCAACAGAACAAGACTCCATCTCAAAAAATAAAAATTAAAATAAAATGTTAGGCTCCCTGGGTCTCTGGCTTAGTCCATTTGTACTGCTTTAACAAAATACCTTAGAATGGTGTAATTCTAATAATTGCTATTAATAAATAATAGCAATTAATAAATAATAGCAATTTCCTTCTCACAGTTCTAGAGGCTGGGAAGTTCAGGGTCAAGGTGGCACCTGACTCCGTTCTGGTAAGGGCGGCTCTCTGCTTCCAAGATGGTGCCTTCTCGCTGCGTCTTCGCATAGCGGAAGGGCAAACACTGTGTCCTCACGTGGCAGAAGAGATAGAAGGGCCAGGCAGCTCTCTGAAGTATCCAGGTTGGAGTCATGGACCTGCATGTTCCCCTCTGACATCCACAGAGTACCTATCATGGTCCTTGGCATGCAGCAGGTGGCCCATAAACGCCTGAATGAACAAACATATAGTAATGGTCGCTAGTACTAGGAATAGCAGCCACCGCAACAGTCCTGTGAGGGAGGCATTACAGATGAGGAAACTGAGGTTTAGGGGCAAGGACCTGCCCATGGTCCCAAAGCTAGGGAGGGACAGGGCTGGGATTCCCACTCCCATCCATCTGGCTCCAGAACCTGAGCTCCTGACCAGGCTGTTCTTATCCTGTCTCAGCCAGTGGCTGCCTGTCTGGACGGATGGACCTAAAGTCAGTCCAGCCAAACAGAGGGAAGCATGATCAACTGTTCTCTAAGTTCCCTGACCCGGAGAGGCTGAGTCCATGGCCCAAGCTCTCCTCTCTCCTCCCCCAGCTCTCCCACCCGTAGACGGTGGCGCGAAGTGGAAGAGTGTGCGGGAACCAAGGAGCTGCTATGTTCTATGATGTGCCTGAAGAAACAGGACCTGTACAACAAGTTCAAGGGACGCGTGCGGACGGTTTCTCCCAGCTCCAAGTCCCCCTGGGTGGAGTCCGAATACCTGGATTACCTTTTTGAAGGTAGGTCTGTGGGTAAGGGACTGAGTGGAAGGCTGTCCATCCCATCGGGGAGCTGTGCTCAGTGCTCAGTGGTTCTGTTCTCCTGACCATCTGTCTCCCACTTCCCCAAAGCAGAGGGCAGCTCCCTGQGCCAGGCCCTTTGAGATGGGGTGTGGGACCAGCAACAGCGAGGGACCATGTCTGGCAGCCTGTCAGGGAGTTAGGGGAGCTCCAGCCAGCACCAGCAATCTCACGTGCACCCTCTGCTAACAATGTTCATTATTTTCAGTTGAGCACCATTTTGGTCATGGACTACACAAGGCACTTTATATGCTTATTCCTATTTTTTTATGTTCAGCTTCTCTCCTTAAAAACAATGTTTAAAACCAATTCTGGGCCAGGCGTGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCAAGGCAGGTGGATCACCTGAGGTCAGGAGTTTGAGACCACCCTGGCCAACATGGCAAAACCCCGTCTTTACTAAAAATACAAAAATTAGCCAGGCTTGGTGGCAGGCACCTGTAATCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCAGGAGGCGGAGGTTGCAGTGAGCCAAGATCACGCCCCTGCACTCCAGCCTGGGCGACAGAGCGTCTCAAAAGAAAAAAATTAATAAACAAAGAAAAAAAAACAAATTCTGTTTGCAAAAGTATTTTCTATACACTGTAGAAATTTGTGGGGTGTGGGGGGGTAAAGATGATAGAAAAAAAAATGTCCCATGCTTACTGGCAGAAATCATGTATTGACATTGGGTGAGGAGGGCACTTTTTTTTTTTCAGTCTATTTTTAATCTTCACAGCAAACTTGTGAGGTTCATTTCCATCAACCTGAGACTCACAGAAGCTAAGAAACTTGATACCGCTAGTAACCAGTGGACTTGATACCGCTAGTAACCGGTGGACATAGATGTGAACTGGATCTTTCTGACCTCGGGCAGGGCCGGGTAACAAGGGGAGGATAAATGCCCAGACAGTGTCCTCAGAGAGCTGAGAGCTGTAACTTGCTGCCCGGGCTTCTCACAGTGTTCAAGGACAAAATAAGGCTTTAAGAGAGAAGAGGGACAGACTGATTGCAGGGCAGCAGGAAGAGATGGTAGAGAAGGAAGAAGAGATGATTCGTGTGGAAAGAAGCTGGCTCGGTGGATGGATAAAAGAAGGGAAGGACAGATGGGTAAGAAGAAAGGGAGGATGGAGGGGATGGAGGAGGAAGCAATGGAAAAATGGGAAGGAAGGAGGTTGGATGGAAGGATAGATGCCTATTAGGAAGGAAATATGTGTGGATAGAGAGATGGAGGATAGGAAGTATGTTAGTCAAGGTTCTCCAGAGAAACTGAACCAATAGGATATATACAGATACACTAAGAGGAGGCCAGCCGGGCGCGGTGGCTCAACCTTGTAATCCCAGCACTTTAGGAGGCCGAGGCGGGCGGATCACGAGGTCAGGAGATCAAGACCATCCTGGCTAACACAGTGAAACCCCGACTCTACTAAAAATACAAAAAAAAATTAGTTGGGCGTGATGATGTGCGCCTGTAGTCCCAGCTGCTGGGGAGGCTAAGGCAGGAGGATGGCGTGAACCCAGGAGGCAGAGCTTGCAGTGAGCTGAGATCGTGCCACTGCACTTCAGCCTGGGTGACAGAGCAAGACTCCGTCTCAAAATAAATAAATAAATAAATAAAAAGAGGCCAGCCATGGTGGCTCACACCTGTAATCTGAGCACTTTGGGAGGCCGAGGCGGATGGATCATTTGAGATCAGGAGTTCAAGACCAGCCTGGCCAACATGGTGAAACCCTGTCTCTACTAAAAATACAAAAGTTACCCGTGTGTGGTGGCACACACCTGTAGTCCCAGCTACTCAGGAGGCTGAGGCAGGAGAATTGCTTGAACTTGGGAAGCAGAGGTTGCAGTGAGCTGAGATCACGACACTGCACTCCAGCCTGGGTGACAGAGCAAGACTTTGTCTCAAAAAAAAAAAATTTATAATAAGAGGAGATTTATTATGGGAATTGGCTCATGCAATCACAGACACAAAAATGTCCCCCAGCATGCAGTCATGGGCTGGACAACCAGGAAAGCTTGTGGTGTGATTCTGTCTGAGTCTGAAGGCCCAAGGCCAGGGGAGCAGTGGTGTAACCCCCAGTCCGAGGCCACAGGCCCGACAATCAGAGGGGCCACTGATATAAGTCCCAGAGTCCAAATGCCGGAGAACAGGAAGCTCCAACGTCCAAGGACAGGAGAAGTTGATGTGCCAGCTCAGGAAGAGAGAATGTGAATGTGCCATTCCTCCTCCATTTTTTGTTCTCTTTGGGCCGTCAGTGGATTGGATGATGCCTGCCCACACTGGTGAGGACAGATCATCACCAAATCTGCCGATTAAAATGTTAATCTCTTCTGGAAAAATCCTCACAGATGGGCCCAGAAATAATGTTTTACTGTCTACCTGGGTATCCCTTAGTGCAGCTAAATTGACACATAAACTTAACCATCACAGGCCAGGCACTGTGGCTCACACCTGTAATCCCATCACTTTGGGAGGCCAAGGTGGGAAGATCCTTTGAGGATGAGGTAGGCAGATCACTTGAGCCTAGGAGTTCAAGACCAGCCTAGGCAACATAGGGAGACCTCGTCTCTACAAAAAAAAAAAAAATTTAAATTCGCTGGGTACGGTGGTGGGCACCTGTGGTCCCAGCTATCTGGGAGGCCAAGGTAGGAGGATGACTTGAGCCCAGGAGGTCAAGGCTGCAGTGAGCCATGATTGTTCCATTGAATTCCAGCCTCGGTGACAGAGCAACACCCTGTCTTAAAGAAAGAAAAAATTTAACCATCACAGAAGGCAGAAGAAAAGGCAGATGGGTGGATGAGATGGGTGGGTAGATAGTATAGAAGAAAAGCGGGACATCCAGGCAGGGAAGGAAGGGCTGGAGCGAAGGAGAAGCAAGGAAGGAAGGAAGGAGAGACAAGAAGGAAGGATGTGTAGAAAGGTGGAAGAGAAAAGAAGAATGGATGTATGGGAAGAATGGATGAGTAGGTTAGAAGGCTCACTGGCTAGATAAAAGGTGAGAAGTATAAATGAATAATAAGAAAGGAGGCATAGGAAGAAAAAAATATTGGTTAGAAAGGATGATTGAGAAGAAAGGGTGGTTGGGAAGGAAGGAAGGAAGGATGGATGGATGGATGGATGGATGGGAAGGAAAGGAAGGATAAGAAGGCAGACAGGAAGGCTCTCTGGCTAGAAGAATGGCAGACAAACCACAATAATTGCTGAATGGGTAGGAATAAGACATTAGAAGAATAAAGGGAAAGACACAAAGATATTTAAAATGTTTTCATTAATTTTTTGCCTCCTCCCTGAATTTCTCCTGATTCTTCAGCCCCACATCCCAAGCCAGGGTGATCCTTCCTGCCTTTACACTCCCTCCACACTTTTTCTGCTCTCATATGTGGCCGTGGTCACTTTCTTTTGGTAGTTTGCATATTTCATTTACCCCAAACTTTCAGCTCCTGAAGGTCAGGATACAAGGAGGCCTCATCTCCGCATTCCCCTCAGCTCCCTTCCTGAAGCTTGATACCTAGTCAGTACCCAGTGGATGTTTCCTAAACATGTAAGTAATGACATCATGAAGAAGCCACATGTTTACCTTGACCACAAACACAGGGCAAAGGTGACTAGTGTGGTCAGAGATCCCTGCTGGCTGGGAATCAGGGAAGGCTGCATGGAAGAAGTGGCATTTTAGTTAGAACTTGAAAGGTGGTGTATTTAGTTTTCTCTGGCTGCCATATTCCTTGTCACATTGCCCTCTCCATCTTCAAGCCACTGGGCAAGGCTAGAAGGCCCTCAACAGACTATCGGTAGGAATGTGGAAGTTGAAGACTCAGAGTGCAGAAAGAAACAAGTAGCATTTTAGAGAAAAGCTAAATCCCCTCCAAGAATACCTCAATCATCGTGAAGAGCCTGTTAGTAGACGCACTAACACTCAAGGCACTGCTTCACAAGGTAAGGAACGTGTAATTGAAAACTTGAGAAAGGAAGAAACTTGTTCTGTACTGGCAGAAAGCTTAGCAGAATTGTGTCCTGCAGTCATATGGGACACAGAGCTTGTAAATGATGAATTTGAATGCTTATCCGAGAAGGTTTCCAAATAAAATGTGGAAGGCACGGCCTGGTTTCTTCCTGCCTCTTATAGTAAAATGCAAGAGGAGAGAGAGAAAATGAGGGAAGAACTTAAACAGAAAGGAACCAGGACTTGATGATTTGGGAGGTTCTCAACCTATGCAAAAAACAATAAAATTAAGAGATTGTAGCTGGGCACAGTGGCTCATGCCTGTAATCCCAGCACTTTGAGAGTCCGAGGCGAGCAGATCACCTGAGGTCAGGAGTTTGAGACCAGCCTGGCCAATGTGGGGAAACTCCGTCTCTACTAAAAATACAAAAATTAGCTGGGTGTGGTGGCGGGCACCTGTAATCCCAGCTACTCAGGAGGCTGAGGTGGGAGGATCACTTGAACCCAAGAGGCGGAGGTTGCAGTGAGCCAAGATCATGCCACTGCACTCCAGCCTGGGTGGGTGACAGAGCAAGACTCCATCTCAAAAAAAAAAAAAAAAAGAGATTGCTCCCAAAAGTGTGACATAGAGAAACAGCCAAGTATGTGATTATACCAAACTTCAGGAAGATAAAAGATCAAAGTACTCAGTCGCTCAAAAGGCTCTTTGAAGAGATTAAGATTATAACTCACAGTCCCCTTCAATCAAACCAGGGGACTTCTAGGAAGCTGAACAGCATTGTCCCTCAGCCATATCAGCTGGAGCCAAAAGTAGAGAAGGGCTTATCTGAAAAAAGGATCTGTGGACCTGGCTTTTATCTAATAATGCAGTGGATTCCCCCATGACATCCATAGGAGACCCGTAAAGTTCCTGAGACGTTTACATCCACAGAAACACTGTTAGCTTGGATTAAATGGAACACAGAGAGTATGAAATCAAAGAAGGCTGTTGGACTCTCCAGTTTCTACTGTTGAGATGCAGACTGGTAAAACTACTTAGCTGCAAACACCTGCTACCTTTAGTGAAAAGGAAGGATATCTCAGACGGTGAAACCAGAAGCTCAAAGGGCAGTGCTAAGAGCGAAAGAGAATTCTTCCCAGGCCTTGAAACCTAATGGAGTTTTCTTGGCTGGATTTTCAAACTGCATTGGACCATGACCTGATTGTCCCTTTCATGTCCCCATGCTTGAGCCAGATTGTCTGCAACTGTTATCCTGTGCCTGTCCCACATTTTATGTTGGGAGCAGAAAACTTTAGTTTTGCTGGCCCACAGATAGAGAGAAACTGTACCCCGAGAGTTGTACTGACTGGACTATGCCCAGAGTCTATTTGACTCTGACTTAGATACTGTTGATTTGGGAATTTGAGTTGATGCTGTAATGAGATGAGACTTTGGGGGACATTGGGATGGAGTGAATGGATTTTGCATTTGAAAGAGATGTGGGTTGGGTAATCCTAGCCCACACCTGTAATCCCAGCACTTTGGGAGGCCGAGGCAGGCAGATCACCTGAGGTCGGCAGTTCGAGACCAGCCTGACCACCATGGAGAAACCCCATCTCTACTAAAAATACAAAATTAGCCAAGCATGGTAGCACATGCCTATAATCCCAGCTACTCGGGAGGCTGAGGCAGTAGAATCGCTTGAACCCGGGAGGCAGAGGTTGCGGTGAGCCGAGATCACGCCATTGCACTCCAGCCTGGGCAACAAGAGTGAACTCCATCTAAAAAAAAAAAAAAAAGAAAGAAAGAGATGTGGATTTTGGGTGGGGGACAGAGGGAAGACCATGGTAGGCAGAATGATCCTCTAAAGGTGCTCTGCCCTAATCCCCAGAAGCTAAGAATATGTTAGATGTCAGTATTGCGTGGCAGTAGGAATCTTAATTAACGTTATAGACTGTTATGQTTTGAATGTCCCCTCTAAAACTCCTGTTGACATTTAATCATCATTGTGATTGCATTAAGAAGTGGCCCTGTTAAAAGGTGATTTAGTCCTTAACAACGCTGCCCCCGTGAATAGATTAAGGTCAGTCTTGCGGGAGTGTGTTTATCAAGAATGGATTGTTAAAAAGTGAGTTCTGGCCAGGGGCAGTGGCTTATGCCACTCAGCACTTTGCGGGGCCAAGACTTGAAGTCAGTTGTTTGAGACCAGCCTGGCCAACATGGTGAAAGTCTGTCTCTACTAAAAAATACAAAAAGTGTCCGGGAGTGGTGGCGGGCGCCTGTAATCCCAGCTGCTCAGGAGGCCGAAGCAGGAGGATCGCATGAATCCGGGAGGCAGAGGTTGCAGTGAGCTGAGATCGCCCCGTTGCACTCCAGCCTGGGTGATAGAGCAAGACTCTGTCTCAAAAAAAAAAAAAAAAGAGGAAAGAAAGAAGAAAGAAAGAGAAAGAAAGAAAAGAAAGAAAAGGAAGGAAGGAAGGAAGGAAGGAAGGAAGGAAGGAAGGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAAGAAAGAAGAAAAAAAGAAAGAAAAAAGAAAGAAAGAAAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAAGAAAAGAAAAGTGAGTTCTGCCCTCTCTTGCTGGCTTACTCTCACCCTCTCTTGCCCTTCCACCTGCCACCATGGGATGACACAGCACAAAGGCCCTCACCAGATGCCAGTGCCATGCTCTTGGACTTCCAAGTCTCCAGAAACATGAGCCAAATACACTTCTGTTCATTATAAATTACCCAGCCTGTGATATTCTGTAATAACAACACAAAATAGACTGAGACATAGATCTTCAAATAGTGAGGTTATCCTGGATAATCCAGATGGGCCCAATCTAATCCCATGAGCCTTTAAAACTTTCTCCAGATGGAGGCAGAAGAGAAGTGGCAGAAGGGGAAGTCAGAGAGATTTGAAGCATAAACAGGACTCCATGGTGCCGTTTCTGGTTTGACGATGGAGTGGTAACGTGATGAAAAATGTGGGTGCCTTCCGGAGCTGAGAGGCTCCCACTAACAATCGGCCAGGAAACAGGGACCACAGCCCTACAGCCACAAAGAACTAAGTTTTGCTGACAACCCAAGGGGGCTTGGAAGTGTCTTCTCCCCCATCGGTTCCAGATGTGAGACCCAGAGCGAAGGAACCAGCTGAGCCCACCTGGACTTCTGACCTAGAGAACTGTGAGATAATAAGTTTGTATCATTTTTAAGGCACTGTGTGTGTGGTAATTTGTTATGACAGCAATAGAAAATGAATCCAGATGGGCAGGATCTGCCAGGCCAGTGACATGTGGAGGGCACCCAGGCGGATGGGATGGCATGAGAGAAGGCAGGTCAGCAATGAGCTTGCCCAGGTCACCTCTCCTCTCTAAGCCTCAGTTTTCCTCTCTATGAAATGAGAGTAGTGATATCTCCCTCCCAGGGTCAGTGCAAGGCTGAAATAACAGATTATAAGGTGCTAGGTGCACAAGAAGTGTTTGAAACATGCTAGTTGCTTTTCCATTTCCAAGAGAGCTCTCTGGTCTTGGGGGATGGAGGCAGTGCGGCCCCTCGGGATTACTGACAGGTCCTGCTCTGTTTCTGCAGTGGAGCCGGCCCCACCTGTCCTGGTGCTCACCCAGACGGAGGAGATCCTGAGTGCCAATGCCACGTACCAGCTGCCCCCCTGCATGCCCCCACTGGATCTGAAGTATGAGGTGGCATTCTGGAAGGAGGGGGCCGGAAACAAGGTGGGAAGCTCCTTTCCTGCCCCCAGGCTAGGCCCGCTCCTCCACCCCTTCTTACTCAGGTTCTTCTCACCCTCCCAGCCTGCTCCTGCACCCCTCCTCCAGGAAGTCTTCCCTGTACACTCCTGACTTCTGGCAGTCAGCCCTAATAAAATCTGATCAAAGTATGATGACCTACAGGAGGCCTGCTTGCCAAGTCAACAGATTCAGTACAGAAAAACTGAAAAATACAGATAAGCTCTAAGAAGCAGACCAAAAGTACCCAGAGATGACCGCACATCACTCTGGTGTATATCCAATTTCAGATTTGTTTTCTGTGTATGCATGTGTGTATAGCTGCATTTATTTATGGCAAGGGCTGGCAGACTTTCCCGAAGAAGGCCAGATAGTCGATATGTTTGGCTTCATGGGCCGTATGTTCGCTCAGGACTACTCAACGCTGCAGTTATAGCACAAAAGGAGCCGTAGCCTATACGTAAATGAATGGGCATCGCTGGGTTCCAGTAAAACTGTTTACAGGCCAGGTGCGGTGGCTCATGCCTGTAATCTCAGTACTTTGGGAGGCCGAGGTGGTGGGAGGATTACCTTAGCCCAGGAGTTCAAGACCAGCCTGGGGAACATGGTGAAACATTATCCCTACAAAAAAAAAAAAAGCTGGGTGTGGTGATGCATGCTTGTGGTCCCAGCTGCTTGGGATGCTGAGGCAGGAGGATCGCTCGAGCCCAGGAAGCAAGGCCACAGTGAGCCATGATCGCACCACTGCACTTTAGTCTGGGCAACAGAGTGAGACCTTGTCTCAAAAAAAACAAAAAATAAAACTTTTTACATAAACAAGTGGCCAACCAGACTTGGTCCCTGGGCCTCTGCTCTTGAATGTTCTTGCTTCCACTAAAGTAACATTCACACTCCCGATTTTTGCATACTCTGGGTTCTGGGGAATATAGATCCGAATCCAGCGTGGTTCCTGCCTTCAAGAACCTCACAAATATTCTAGACCAGCACTGCCCAATAGAAAGAAATATAATGCAAGCCACATGTGCAGTTTTAAGTGTTCCATGTTAAATTAAGTAAAAAGAGACGGGTAAATCGAATTTTAATAACAGATTTTACTTCATCCAATTGAATGGTATCATTTCAATGAGCAATTCTGATAGTGATTGAGATCTTTTACATTCTTTTTCACTACGTCTTTAAAATCTGATGTGTGTTTTGTACTTGGAACACTTCTCAGTGTGGACCAGATGCATTTCACATACTCAGTAGTCACGCGTGGCCAGTGCCTTCCATACCACACAGTGCAGCATCTGTAGAGGTTTCCTCCACTGCTGATAGACTAGGAGACCCCAAGATGGAAAGCCTGAAGAATCTGCTCCTCGAAGTAGGGACCTTAATGGGGTGCACGCCAGGGCGACCCCAAGTGGTAGGCTGCTTTTGAACCATGGCTATCCCTACCTCTAGACTCAGCTGAAAAGAACTCAGGTAGTCTTGGGAAGTGCTTCCTCAATGCTTAAACTTTAATGCAGGAAAAGAATAGAAAGTTCAGGCAAGGAGGGAGGATCACTTGAGGCTGGGAGTTCGAGACCAGCCTGGGCAACAGCAAGACCTTGCCTATACAAAAAATAATTTTAAAAAATTACCCAGGTATGGTGGTGTGGATCTGTAGTCCCTAGTTACTTGGAGAGCTGAGGTAGGAGGATCGCTTGAGCCCAGGAGTTTGAGGCTGCAGTGAGCTGTGATCACACCACTGCACTTTGGCCTGGGTGACAGAACCAAACCCTATCCCCTACAAAAAAACAAAAAAAAAAAACAAAAAAAAACACCCTACCATGTCTGCCAACCCCACTCTGTCCTGGCTGTGTGAAACCAGTCCCCACAGCAGCTCTGCCACTCTCTGCTTCTTTTCCAAACAGACCCTATTTCCAGTCACTCCCCATGGCCAGCCAGTCCAGATCACTCTCCAGCCAGCTGCCAGCGAACACCACTGCCTCAGTGCCAGAACCATCTACACGTTCAGTGTCCCGAAATACAGCAAGTTCTCTAAGCCCACCTGCTTCTTGCTGGAGGTCCCAGGTGGGTATCAAGTGGTGCAGAAGGAGAAACTTTCCCTCTGGGCCTTGGGAGCTTCGTGACACAGTGGTTAAGAACATGAGCCTAGAGATAGACTCGCCTGGATTAAAACCACACTCATTGTGTGTCTTTGGGCAGCTTACATAATGCCCCGAACCTTGGTTTGCACAGTCTGCAGGATGGGTTTATTCTTGTGAGGATTAAATAGGGTCATGTATGTGAAGCACTCGGCACAGGTGCAGTTGTAGACAAGAGCCATTGTTGTTTCTCTCATTGTTATTTTTCCTTCCTTAGAAGCCAACTGGGCTTTCCTGGTGCTGCCATCGCTTCTGATACTGCTGTTAGTAATTGCCGCAGGGGGTGTGATCTGGAAGACCCTCATGGGGAACCCCTGGTTTCAGCGGGCAAAGATGCCACGGGCCCTGGTATAGCAAATCTGGGGGTGTGCGGCAGGTGGGGAGGGGTTGAGAGTAAGGGAGTGGGGCTGGAGCTATGAGTTGTTCAGATAGAATATCAAGATGGTCCAGACTCTTGGACCAAAACATCTATCTTTGTGTCTGAATTTCCACCATTAGTAATGCATTCATTTAGTCCTGAATAAAATGGCAAACAGGCCCTGGAGGGAGCAGTGCCTTAAGTTCCTTTGAGATAAATAACTTCACCTCTGCTAAGGATGTGTCAGCTGCTGAGAGCAGAGCCCCTGGCCTTGGACCTCAGGAGAGACACTCAAAAGGGGAGGAGAGGAGGCACCAAAGGGGACATCTTAAAAGAGTTCCPATTTTTAGTTCACACTTTAACCCAGGATAAGCTGTGTCCTGGCTGACCTTGGAGTTTCTTCCCTGGTCTGCTGCGTCTCTCCCTTAGAACCTAGGGGCGAGCTGGGGCAGGGGAAGCCCAGGAGGTGATATAGGTCGGCCCTGTTCAGATGAGGGCTGGCAGGGGCAGCTTGGGCATATGCGAGGCTCCGATGGGCATGGGGGCTTTGAGGATGGATTCTGAGTGTCCCTGCATCGTGGCAGGGTGGCAAAGGGAGCATTTCCAAATTTCCTGGCTCCAGGATCTGTGGGAGAATCCCACTAACTGTCAGGGTGACAACCTCGGGTAGACATGTCTGTGCCCTGCCCCGTGCCCTCAGCCTTCCTGTTAAGAGCACACCAGCTGGATTTGCAACTCCCAGCGCCTGCACCCAATGGGCTTTCTCTGGCCTCTGGAGCCCACATTGCCCCTGCATGTGGCAGGCTGCAAGTGTCACAGCCACCAGCTCTTCCATTCCTCAACAATGACTGTGGGTAAATAGCCCAGGAGCGTCCCCCTCCTGGGATGGTTCTGAGGTGCGTGTGCCCAGTGGCTCCCTGAGTTGCCAGCAGGATTAAGTGCCAGTAGCCCTAGTGGTCAGCTGCTTGATAACACCCTGCTTCCTGGCTGCTCCCCCAGTCCCATCTGGTGTGTTCTGGGATCATCTCCCAAAGAAACTGCTTACACTTGAAGCCTTGTCTGAGGTCTGTTTCTAGGGGAATTCAGATGACGATAATTATGCTTCAGGAAAGCCTAAATTTTCTGCTTTTCTCTCCCCTACCCAAATCAGGACTTTTCTGGACACACACACCCTGTGGCAACCTTTCAGCCCAGCAGACCAGAGTCCGTGAATGACTTGTTCCTCTGTCCCCAAAAGGAACTGACCAGAGGGGTCAGGCCGACGCCTCGAGTCAGGGCCCCAGCCACCCAACAGACAAGATGGAAGAAGGACCTTGCAGAGGACGAAGAGGAGGAGGATGAGGAGGACACAGAAGATGGCGTCAGCTTCCAGCCCTACATTGAACCACCTTCTTTCCTGGGGCAAGAGCACCAGGCTCCAGGGCACTCGGAGGCTGGTGGGGTGGACTCAGGGAGGCCCAGGGCTCCTCTGGTCCCAAGCGAAGGCTCCTCTGCTTGGGATTCTTCAGACAGAAGCTGGGCCAGCACTGTGGACTCCTCCTGGGACAGGGCTGGGTCCTCTGGCTATTTGGCTGAGAAGGGGCCAGGCCAAGGGCCGGGTGGGGATGGGCACCAAGAATCTCTCCCACCACCTGAATTCTCCAAGGACTCGGGTTTCCTGGAAGAGCTCCCAGAAGATAACCTCTCCTCCTGGGCCACCTGGGGCACCTTACCACCGGAGCCGAATCTGGTCCCTGGGGGACCCCCAGTTTCTCTTCAGACACTGACCTTCTGCTGGGAAAGCAGCCCTGAGGAGGAAGAGGAGGCGAGGGAATCAGAAATTGAGGACAGCGATGCGGGCAGCTGGGGGGCTGAGAGCACCCAGAGGACCGAGGACAGGGGCCGGACATTGGGGCATTACATGGCCAGGTGAGCTGTCCCCCGACATCCCACCGAATCTGATGCTGCTGCTGCCTTTGCAAGGACTACTGGGCTTCCCAAGAAACTCAAGAGCCTCCGTACCTCCCCTGGGCGGCGGAGGGGCATTGCACTTCCGGGAAGCCCACCTAGCGGCTGTTTGCCTGTCGGGCTGAGCAATAACATGCCCCTCCCTCCTGTGACCCGCCCTCTTTAGGCTGAGCTATAAGAGGGGTGGACACAGGGTGGGCTGAGGTCAGAGGTTGGTGGGGTGTCATCACCCCCATTGTCCCTAGGGTGACAGGCCAGGGGGAAAAATTATCCCCGGACAACATGAAACAGGTGAGGTCAGGTCACTGCGGACATCAAGGGCGGACACCACCAAGGGGCCCTCTGGAACTTGAGACCACTGGAGGCACACCTGCTATACCTCATGCCTTTCCCAGCAGCCACTGAACTCCCCCATCCCAGGGCTCAGCCTCCTGATTCATGGGTCCCCTAGTTAGGCCCAGATAAAAATCCAGTTGGCTGAGGGTTTTGGATGGGAAGGGAAGGGTGGCTGTCCTCAAATCCTGGTCTTTGGAGTCATGGCACTGTACGGTTTTAGTGTCAGACAGACCGGGGTTCAAATCCCAGCTCTGCTCTTCACTGGTTGTATGATCTTGGGGAAGACATCTTCCTTCTCTGCCTCGGCTTCCTCATCTGCAGCTACGCCTGGGTGTGGTGAGGGTTCTAGGGGATCTCAGATGTGTGTAGCACGGAGCCTGCTGTGTCCTGGGTGCTCTCTACGTGGTGGCCGGTAGAATTCTCCATCTATCCAGGCTCCAGGAGACCCCTGGGCATCTCCCACCTGTGGCCCCTAAACCCAGAGTGACTGAGAGCACTTACCATTCAGCTTGTCTCATCCCCAGTCTACCTCCTTCCTTCTACCCTCACTGCCTCCCAGTCAGGAGAGTGAGCTCTCAGAAGCCAGAGCCCCACCCAAGGGGACCCTGGTCTCTCCGCCTTCACCTAGCAATGGGAACCCTGCTTCCCAGGGGAGGAACCAACTGCTCCACCTTCTAGGGACCCAGTTTGTTGGAGTAGGACAGTAACATGGCAGGAATCGGACTTCTGGGCCTGTAATCCCAGTTTGGATGGCACGTTAGACTCTTGGTTGACCGTTGTGGTCCTTAGAAGTCCCATTCTCCCTTCCAGTTATGAGAAACCAATGCCTTCTAGATTCAGGTGACTATCCTTACCTGGGGGTGCTGATGCATCCTCAGTTAACCTACACCCACCTGAATATAGATGAGCGTAGCTGAGTTTTCACCCGTAGGACCGAAGTGTTTTGTGGTGGAGTATCTGAACAACCTTGGCTCTGTGGCCATTCAACCTGCCAGGACTAACATTTCTGGATTTGTGAAGAAGGGATCTTCAAAGCCATTGAACCCACAGAGCTGTGTTGCTTTAAAGCCACCACAAGGGTACAGCATTAAATGGCAGAACTGGAAAAGCTTCTTAGGGCATCTCATCCAGGGATTCTCAAACCATGTCCCCCAGAGGCCTTGGGCTGCAGTTGCAGGGGGCGCCATGGGGCTATAGGAGCCTCCCACTTTCACCAGAGCAGCCTCACTGTGCCCTGATTCACACACTGTGGCTTTCCACGTGAGGTTTTGTTTAGAGGGATCCACTACTCAAGAAAAAGTTAGCAAACCACTCCTTTTGTTGCAAAGGAGCTGAGGTCAAGGGTGGCAAAGGCACTTGTCCAAGGTCGCCCAGCAGTGCTGCTCTGATGACTTGTGCACATCCCCAAGGGTAAGAGCTTCGATCTCTGCACAGCCGGGCCAACCTCTGACCCCTTGTCCATGTCAGTAAAATATGAAGGTCACAGCCAGGATTTCTAAGGGTCAGGAGGCCTTCACCGCTGCTGGGGCACACACACACACATGCATACACACATACGACACACACCTGTGTCTCCCCAGGGGTTTTCCCTGCAGTGAGGCTTGTCCAGATGATTGAGCCCAGGAGAGGAAGAACAAACAAACTACGGAGCTGGGGAGGGCTGTGGCTTGGGGCCAGCTCCCAGGGAAATTCCCAGACCTGTACCGATGTTCTCTCTGGCACCAGCCGAGCTGCTTCGTGGAGGTAACTTCAAAAAAGTAAAAGCTATCATCAGCATCATCTTAGACTTGTATGAAATAACCACTCCGTTTCTATTCTTAAACCTTACCATTTTTGTTTTGTTTTGTTTTTTTGAGTCGGAGTTTTGTTCTTGTTGCCTAGGCTGGAGTGCAGTGGTGCGATCTCGGCTCACTGCAACCTCCACCTCCCGGGTTCAAGTGATTCTCCTOCCTCAGCCTCCCAAGTAGCTGGGATTACAGGCACCCGCCACCACACCTGGCTAATTTTTTTGTATTTTTAGTAGAGATGGGGTTTCACCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCAGCCAAACCTTACTATTTTTTTAAAGAATTTTTTCCAGAGTTTAATTTCTGACATAGCTTAAGTTTTCCAGTAACTCTAAACTCCATCTCCTTTATCGTCATTAAGTCATTCACAAAAAGCCAGGAGAAGCATTTGGAAAGGGCATGATAATCAGTATAATAATT

[0063] Table 8 presents a correlation between the genomic sequence shownin Table 7 and the locations of the corresponding regions of the cDNAsequence shown in Table 1. TABLE 8 Region in Genomic SequenceCorresponding Region Sequence of Table 7 Attribute Length in cDNAsequence   1-2000 5′ sequence 2000 — 2001-2058 Exon #1 58  1-582059-8391 Intron #1 6333 — 8392-8515 Exon #2 124  59-182  8516-19645Intron #2 11130 — 19646-19830 Exon #3 185 183-367 19831-27533 Intron #37703 — 27534-27676 Exon #4 143 368-510 27677-29583 Intron #4 1907 —29584-29743 Exon #5 160 511-670 29744-30034 Intron #5 291 — 30035-30165Exon #6 131 671-801 30166-31325 Intron #6 1160 — 31326-32084 Exon #7 759 802-1560 32085-32087 Stop 3 1561-1563 32088-34757 3′ sequence 2667 —

[0064] Several sequence polymorphisms have been identified in thesequence shown in Table 7. These are summarized in the Table 9: TABLE 9SNP Position SNP Changes variation 32959 allele = “C” allele = “A”variation 31266 allele = “C” allele = “T” variation 30960 allele = “T”allele = “C” variation 29048 allele = “C” allele = “T” variation 28753allele = “G” allele = “A” variation 23830 allele = “G” allele = “A”variation  8811 allele = “C” allele = “T”

[0065] CRF2-like nucleic acids and polypeptides of the invention(including those shown in Table 1) are referred to herein as “CRF2-13”nucleic acids and polypeptides.

[0066] A CRF2-13 nucleic acid, and the encoded polypeptide, according tothe invention are useful in a variety of applications and contexts. Forexample, sequence comparison reveals that the disclosed CRF2-13 nucleicacid (Table 1) encodes a Type II cytokine receptor. One or more secretedreceptor chains may be associated with, and/or modulate the activity of,another membrane bound member of CRF2, or a membrane bound receptor ofanother family. Alternatively, or in addition, the receptor chainsdisclosed herein may act alone or in combination with another solublereceptor. In effect, the receptor can also be a ligand.

[0067] A soluble form of the CRF2-13 polypeptide of the invention (e.g.,a polypeptide that includes amino acids 21-230, amino acids of SEQ IDNO:2) may additionally be used as a soluble receptor antagonist. Solublereceptor antagonists that block the activity of specific cytokines,e.g., TNF, are known in the art. A soluble CRF2-13 polypeptide of theinvention can similarly block the activity of a cytokine that actsthrough a CRF2 member. Examples of such polypeptides include IL-10,IL-19, IL-20, IL-22, AK155, mda-7 or an interferon, such as interferonalpha, interferon beta, or interferon gamma. In one embodiment, asoluble CRF2-13 polypeptide of the invention is used to antagonize thefunction of IL-22. IL-22 is distantly related in sequence to IL-10 andis produced by activated T cells. IL-22 signaling into a cell ismediated by its receptor chains, IL-22R and CRF2-4, both members of theCRF2 family. The CRF2-4 receptor was originally reported to serve as asecond component in IL-10 signaling. IL-22 has been reported to inhibitIL-4 production from human Th2 T cells and to induce acute phaseproteins in the liver of mice.

[0068] CRF2-13 nucleic acids and polypeptides according to the inventionmay additionally be used to identify cell types that make the inventionor bind to the invention in a population of cells. The CRF2-13 nucleicacids and polypeptides can also be used for immunomodulation,inflammation, immunosuppression, allergy, asthma, autoimmunity(including rheumatoid arthritis and multiple sclerosis), repair ofvascular smooth muscle cell after vascular injury or disease,transplantation and cancer based on the ligand that associates with thissoluble receptor, alone or in conjunction with another receptor, and theimpact that this ligand has on the above mechanisms and/or pathologies.

[0069] For example, a CRF2-13 polypeptide and/or soluble form of aCRF2-13 polypeptide of the invention may exhibit one or more of thefollowing activities: (1) modulation,-e.g., it may antagonize a signaltransduction pathway mediated by a cytokine (such as IL-10 or IL-22);(2) modulation of cytokine production and/or secretion (e.g., productionand/or secretion of a proinflammatory cytokine); (3) modulation oflymphokine production and/or secretion; (4) modulation of expression oractivity of nuclear transcription factors (5) competition with cytokinereceptors for cytokine ligands; (6) modulation of cell proliferation,development or differentiation, e.g., cytokine-stimulated (such as IL-10or IL-22) production, development, or differentiation; (7) modulation ofcellular immune responses; modulation of cytokine-meditatedproinflammatory actions; and/or promotion and/or potentiation of immunereactions.

[0070] A CRF2-13 polypeptide of the invention may directly, byassociation with a membrane bound receptor, or indirectly, by itsassociation with a soluble ligand affect or effect one or more of thefollowing cell types: circulating or tissue-associated cells: T cells, Bcells, NK cells, NK T cells, dendritic cells, macrophages, monocytes,neutrophils, mast cells, basophils, eosinophils, as well as cells in therespiratory tract, pancreas, kidney, liver, small and large intestine. ACRF2-13 polypeptide of the invention may additionally modulateupregulation of humoral immune responses and cell-mediated immunereactions; modulate the synthesis of proinflammatory cytokines andchemokines; and modulate inflammatory responses associated with injury,sepsis, gastrointestinal and cardiovascular disease, or inflammationfollowing surgery.

[0071] For efficient production of the protein, it is preferable toplace the CRF2-13 sequences under the control of expression controlsequences optimized for expression in a desired host. For example, thesequences may include optimized transcriptional and/or translationalregulatory sequences (such as altered Kozak sequences). In addition, themature amino terminus of a CRF2-13 protein may be operably linked to anon-CRF2-13 signal sequence based on a hypothetical or empiricallydetermined of the mature amino terminal end of the protein.

[0072] A CRF2-13 fusion protein can be used to identify and determinebinding partners using assays known in the art. These assays include,e.g., either histological, immunochemical, BIACORE or cell biology basedassays.

[0073] Assays can also be performed in order to determine whether aCRF2-13 protein of the invention associates with cell types that alreadyexpress other members of the CRF2 family. A CRF2-13 of the invention canalso be examined for its ability to modulate the activity of known ornovel cytokines (e.g., by inhibiting or otherwise antagonizing thefunctions of a cytokine).

[0074] For example, several novel IL-10 like molecules have been cloned.IL-22 is one of these molecules. It has been reported that this moleculeblocks the production of IL-4 by Th2 cells (human) and initiates anacute phase response (mice). A finding that CRF2-13 binds to andinhibits IL-22 (or other IL-10 like molecules) indicates a CRF2-13invention can be used to treat or prevent diseases associated with highlevels of the IL-22 polypeptide.

[0075] It is also contemplated that a CRF2-13 polypeptide of theinvention associates with other receptors and/or their associatedcytokines within the CRF2 family. For example, a CRF2-13 of theinvention may associate with either chain of the IL-22R and affect thefunction of the receptor or the IL-22 ligand.

[0076] Also within the invention is a nucleic acid that encodes apolypeptide that includes amino acid sequences 21-520 of SEQ ID NO:2,e.g., a nucleic acids 61-1560 of SEQ ID NO:1. Examples of such nucleicacid molecules are that encode polypeptides with the amino acidsequences of SEQ ID NO:2.

[0077] Also included in the invention is a vector containing one or moreof the nucleic acids described herein, and a cell containing the vectorsor nucleic acids described herein.

[0078] The invention is also directed to host cells transformed with avector comprising any of the nucleic acid molecules described above.

[0079] In another aspect, the invention includes a pharmaceuticalcomposition that includes an CRF2-13 nucleic acid and a pharmaceuticallyacceptable carrier or diluent.

[0080] In a further aspect, the invention includes a substantiallypurified CRF2-13 polypeptide, e.g., any of the CRF2-13 polypeptidesencoded by an CRF2-13 nucleic acid, and fragments, homologs, analogs,and derivatives thereof. The invention also includes a pharmaceuticalcomposition that includes an CRF2-13 polypeptide and a pharmaceuticallyacceptable carrier or diluent.

[0081] In still a further aspect, the invention provides an antibodythat binds specifically to an CRF2-13 polypeptide. The antibody can be,e.g., a monoclonal or polyclonal antibody, and fragments, homologs,analogs, and derivatives thereof. The invention also includes apharmaceutical composition including CRF2-13 antibody and apharmaceutically acceptable carrier or diluent. The invention is alsodirected to isolated antibodies that bind to an epitope on a polypeptideencoded by any of the nucleic acid molecules described above.

[0082] The invention also includes kits comprising any of thepharmaceutical compositions described above.

[0083] The invention further provides a method for producing an CRF2-13polypeptide by providing a cell containing an CRF2-13 nucleic acid,e.g., a vector that includes an CRF2-13 nucleic acid, and culturing thecell under conditions sufficient to express the CRF2-13 polypeptideencoded by the nucleic acid. The expressed CRF2-13 polypeptide is thenrecovered from the cell. Preferably, the cell produces little or noendogenous CRF2-13 polypeptide. The cell can be, e.g., a prokaryoticcell or eukaryotic cell.

[0084] The invention is also directed to methods of identifying anCRF2-13 polypeptide or nucleic acid in a sample by contacting the samplewith a compound that specifically binds to the polypeptide or nucleicacid, and detecting complex formation, if present.

[0085] The invention further provides methods of identifying a compoundthat modulates the activity of an CRF2-13 polypeptide by contacting anCRF2-13 polypeptide with a compound and determining whether the CRF2-13polypeptide activity is modified.

[0086] The invention is also directed to compounds that modulate CRF2-13polypeptide activity identified by contacting an CRF2-13 polypeptidewith the compound and determining whether the compound modifies activityof the CRF2-13 polypeptide, binds to the CRF2-13 polypeptide, or bindsto a nucleic acid molecule encoding an CRF2-13 polypeptide.

[0087] In another aspect, the invention provides a method of determiningthe presence of or predisposition of an CRF2-13-associated disorder in asubject. The method includes providing a sample from the subject andmeasuring the amount of CRF2-13 polypeptide in the subject sample. Theamount of CRF2-13 polypeptide in the subject sample is then compared tothe amount of CRF2-13 polypeptide in a control sample. An alteration inthe amount of CRF2-13 polypeptide in the subject protein sample relativeto the amount of CRF2-13 polypeptide in the control protein sampleindicates the subject has a tissue proliferation-associated condition. Acontrol sample is preferably taken from a matched individual, i.e., anindividual of similar age, sex, or other general condition but who isnot suspected of having a tissue proliferation-associated condition.Alternatively, the control sample may be taken from the subject at atime when the subject is not suspected of having a tissueproliferation-associated disorder. In some embodiments, the CRF2-13 isdetected using an CRF2-13 antibody.

[0088] In a further aspect, the invention provides a method ofdetermining the presence of or predisposition of an CRF2-13-associateddisorder in a subject. The method includes providing a nucleic acidsample, e.g., RNA or DNA, or both, from the subject and measuring theamount of the CRF2-13 nucleic acid in the subject nucleic acid sample.The amount of CRF2-13 nucleic acid sample in the subject nucleic acid isthen compared to the amount of an CRF2-13 nucleic acid in a controlsample. An alteration in the amount of CRF2-13 nucleic acid in thesample relative to the amount of CRF2-13 in the control sample indicatesthe subject has a tissue proliferation-associated disorder.

[0089] In a still further aspect, the invention provides a method oftreating or preventing or delaying an CRF2-13-associated disorder. Themethod includes administering to a subject in which such treatment orprevention or delay is desired an CRF2-13 nucleic acid, an CRF2-13polypeptide, or an CRF2-13 antibody in an amount sufficient to treat,prevent, or delay a tissue proliferation-associated disorder in thesubject. Examples of such disorders include rheumatoid arthritis andmultiple sclerosis.

[0090] CRF2-1 Nucleic Acids

[0091] The nucleic acids of the invention include those that encode aCRF2-13 polypeptide or protein. As used herein, the terms polypeptideand protein are interchangeable.

[0092] In some embodiments, a CRF2-13 nucleic acid encodes a matureCRF2-13 polypeptide. As used herein, a “mature” form of a polypeptide orprotein described herein relates to the product of a naturally occurringpolypeptide or precursor form or proprotein. An example of a CRF2-13nucleic acid encoding a mature form of a CRF2-13 polypeptide is anucleotide sequence encoding amino acids 21-520 of SEQ ID NO:2 (e.g.,nucleotides 61-1560 of SEQ ID NO:1). The naturally occurringpolypeptide, precursor or proprotein includes, by way of nonlimitingexample, the full length gene product, encoded by the correspondinggene. Alternatively, it may be defined as the polypeptide, precursor orproprotein encoded by an open reading frame described herein. Theproduct “mature” form arises, again by way of nonlimiting example, as aresult of one or more naturally occurring processing steps that may takeplace within the cell in which the gene product arises. Examples of suchprocessing steps leading to a “mature” form of a polypeptide or proteininclude the cleavage of the N-terminal methionine residue encoded by theinitiation codon of an open reading frame, or the proteolytic cleavageof a signal peptide or leader sequence. Thus a mature form arising froma precursor polypeptide or protein that has residues 1 to N, whereresidue 1 is the N-terminal methionine, would have residues 2 through Nremaining after removal of the N-terminal methionine. Alternatively, amature form arising from a precursor polypeptide or protein havingresidues 1 to N, in which an N-terminal signal sequence from residue 1to residue M is cleaved, would have the residues from residue M+1 toresidue N remaining. Further as used herein, a “mature” form of apolypeptide or protein may arise from a step of post-translationalmodification other than a proteolytic cleavage event. Such additionalprocesses include, by way of non-limiting example, glycosylation,myristoylation or phosphorylation. In general, a mature polypeptide orprotein may result from the operation of only one of these processes, ora combination of any of them.

[0093] Among the CRF2-13 nucleic acids of the invenation are the nucleicacid whose sequence is provided in nucleotides 1-1560 of SEQ ID NO:1,SEQ ID NO:1 itself, or a fragment of one of these sequences.Additionally, the invention includes mutant or variant nucleic acids ofSEQ ID NO:1, or a fragment thereof, any of whose bases may be changedfrom the corresponding bases shown in SEQ ID NO:1, while still encodinga protein that maintains at least one of its CRF2-13-like activities andphysiological functions (ie., modulating angiogenesis, neuronaldevelopment). The invention further includes the complement of thenucleic acid sequence of SEQ ID NO:1, including fragments, derivatives,analogs and homologs thereof. The invention additionally includesnucleic acids or nucleic acid fragments, or complements thereto, whosestructures include chemical modifications.

[0094] One aspect of the invention pertains to isolated nucleic acidmolecules that encode CRF2-13 proteins or biologically active portionsthereof. Also included are nucleic acid fragments sufficient for use ashybridization probes to identify CRF2-13-encoding nucleic acids (e.g.,CRF2-13 mRNA) and fragments for use as polymerase chain reaction (PCR)primers for the amplification or mutation of CRF2-13 nucleic acidmolecules. As used herein, the term “nucleic acid molecule” is intendedto include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules(e.g., mRNA), analogs of the DNA or RNA generated using nucleotideanalogs, and derivatives, fragments and homologs thereof. The nucleicacid molecule can be single-stranded or double-stranded, but preferablyis double-stranded DNA.

[0095] “Probes” refer to nucleic acid sequences of variable length,preferably between at least about 10 nucleotides (nt), 100 nt, or asmany as about, e.g., 6,000 nt, depending on use. Probes are used in thedetection of identical, similar, or complementary nucleic acidsequences. Longer length probes are usually obtained from a natural orrecombinant source, are highly specific and much slower to hybridizethan oligomers. Probes may be single- or double-stranded and designed tohave specificity in PCR, membrane-based hybridization technologies, orELISA-like technologies.

[0096] An “isolated” nucleic acid molecule is one that is separated fromother nucleic acid molecules that are present in the natural source ofthe nucleic acid. Examples of isolated nucleic acid molecules include,but are not limited to, recombinant DNA molecules contained in a vector,recombinant DNA molecules maintained in a heterologous host cell,partially or substantially purified nucleic acid molecules, andsynthetic DNA or RNA molecules. Preferably, an “isolated” nucleic acidis free of sequences which naturally flank the nucleic acid (i.e.,sequences located at the 5′ and 3′ ends of the nucleic acid) in thegenomic DNA of the organism from which the nucleic acid is derived. Forexample, in various embodiments, the isolated CRF2-13 nucleic acidmolecule can contain less than about 50 kb, 25 kb, 5 kb, 4 kb, 3 kb, 2kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flankthe nucleic acid molecule in genomic DNA of the cell from which thenucleic acid is derived. Moreover, an “isolated” nucleic acid molecule,such as a cDNA molecule, can be substantially free of other cellularmaterial or culture medium when produced by recombinant techniques, orof chemical precursors or other chemicals when chemically synthesized.

[0097] A nucleic acid molecule of the present invention, e.g., a nucleicacid molecule having the nucleotide sequence of SEQ ID NO:1, or acomplement thereof, can be isolated using standard molecular biologytechniques and the sequence information provided herein. Using all or aportion of the nucleic acid sequence of SEQ ID NO:1 as a hybridizationprobe, CRF2-13 nucleic acid sequences can be isolated using standardhybridization and cloning techniques (e.g., as described in Sambrook etal., eds., MOLECULAR CLONING: A LABORATORY MANUAL 2^(nd) Ed., ColdSpring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989; andAusubel, et al., eds., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, JohnWiley & Sons, New York, N.Y., 1993.)

[0098] A nucleic acid of the invention can be amplified using cDNA, mRNAor alternatively, genomic DNA, as a template and appropriateoligonucleotide primers according to standard PCR amplificationtechniques. The nucleic acid so amplified can be cloned into anappropriate vector and characterized by DNA sequence analysis.Furthermore, oligonucleotides corresponding to CRF2-13 nucleotidesequences can be prepared by standard synthetic techniques, e.g., usingan automated DNA synthesizer.

[0099] As used herein, the term “oligonucleotide” refers to a series oflinked nucleotide residues, which oligonucleotide has a sufficientnumber of nucleotide bases to be used in a PCR reaction. A shortoligonucleotide sequence may be based on, or designed from, a genomic orcDNA sequence and is used to amplify, confirm, or reveal the presence ofan identical, similar or complementary DNA or RNA in a particular cellor tissue. Oligonucleotides comprise portions of a nucleic acid sequencehaving about 10 nt, 50 nt, or 100 nt in length, preferably about 15 ntto 30 nt in length. In one embodiment, an oligonucleotide comprising anucleic acid molecule less than 100 nt in length would further compriseat lease 6 contiguous nucleotides of SEQ ID NO:1, or a complementthereof. Oligonucleotides may be chemically synthesized and may be usedas probes.

[0100] In another embodiment, an isolated nucleic acid molecule of theinvention comprises a nucleic acid molecule that is a complement of thenucleotide sequence shown in SEQ ID NO:1, or a portion of thisnucleotide sequence. A nucleic acid molecule that is complementary tothe nucleotide sequence shown in SEQ ID NO:1 is one that is sufficientlycomplementary to the nucleotide sequence shown in SEQ ID NO:1 that itcan hydrogen bond with little or no mismatches to the nucleotidesequence shown in SEQ ID NO:1, thereby forming a stable duplex.

[0101] As used herein, the term “complementary” refers to Watson-Crickor Hoogsteen base pairing between nucleotide units of a nucleic acidmolecule, and the term “binding” means the physical or chemicalinteraction between two polypeptides or compounds or associatedpolypeptides or compounds or combinations thereof. Binding includesionic, non-ionic, Von der Waals, hydrophobic interactions, etc. Aphysical interaction can be either direct or indirect. Indirectinteractions may be through or due to the effects of another polypeptideor compound. Direct binding refers to interactions that do not takeplace through, or due to, the effect of another polypeptide or compound,but instead are without other substantial chemical intermediates.

[0102] Moreover, the nucleic acid molecule of the invention can compriseonly a portion of the nucleic acid sequence of SEQ ID NO:1, e g., afragment that can be used as a probe or primer, or a fragment encoding abiologically active portion of CRF2-13. Fragments provided herein aredefined as sequences of at least 6 (contiguous) nucleic acids or atleast 4 (contiguous) amino acids, a length sufficient to allow forspecific hybridization in the case of nucleic acids or for specificrecognition of an epitope in the case of amino acids, respectively, andare at most some portion less than a full length sequence. Fragments maybe derived from any contiguous portion of a nucleic acid or amino acidsequence of choice. Derivatives are nucleic acid sequences or amino acidsequences formed from the native compounds either directly or bymodification or partial substitution. Analogs are nucleic acid sequencesor amino acid sequences that have a structure similar to, but notidentical to, the native compound but differs from it in respect tocertain components or side chains. Analogs may be synthetic or from adifferent evolutionary origin and may have a similar or oppositemetabolic activity compared to wild type.

[0103] Derivatives and analogs may be full length or other than fulllength, if the derivative or analog contains a modified nucleic acid oramino acid, as described below. Derivatives or analogs of the nucleicacids or proteins of the invention include, but are not limited to,molecules comprising regions that are substantially homologous to thenucleic acids or proteins of the invention, in various embodiments, byat least about 70%, 80%, 85%, 90%, 95%, 98%, or even 99% identity (witha preferred identity of 80-99%) over a nucleic acid or amino acidsequence of identical size or when compared to an aligned sequence inwhich the alignment is done by a computer homology program known in theart, or whose encoding nucleic acid is capable of hybridizing to thecomplement of a sequence encoding the aforementioned proteins understringent, moderately stringent, or low stringent conditions. See e.g.Ausubel, et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley &Sons, New York, N.Y., 1993, and below. An exemplary program is the Gapprogram (Wisconsin Sequence Analysis Package, Version 8 for UNIX,Genetics Computer Group, University Research Park, Madison, Wis.) usingthe default settings, which uses the algorithm of Smith and Waterman(Adv. Appl. Math., 1981, 2: 482-489, which is incorporated herein byreference in its entirety).

[0104] A “homologous nucleic acid sequence” or “homologous amino acidsequence,” or variations thereof, refer to sequences characterized by ahomology at the nucleotide level or amino acid level as discussed above.Homologous nucleotide sequences encode those sequences coding forisoforms of a CRF2-13 polypeptide. Isoforms can be expressed indifferent tissues of the same organism as a result of, for example,alternative splicing of RNA. Alternatively, isoforms can be encoded bydifferent genes. In the present invention, homologous nucleotidesequences include nucleotide sequences encoding for a CRF2-13polypeptide of species other than humans, including, but not limited to,mammals, and thus can include, e.g., mouse, rat, rabbit, dog, cat cow,horse, and other organisms. Homologous nucleotide sequences alsoinclude, but are not limited to, naturally occurring allelic variationsand mutations of the nucleotide sequences set forth herein. A homologousnucleotide sequence does not, however, include the nucleotide sequenceencoding human CRF2-13 protein. Homologous nucleic acid sequencesinclude those nucleic acid sequences that encode conservative amino acidsubstitutions (see below) in SEQ ID NO:2, as well as a polypeptidehaving CRF2-13 activity. Biological activities of the CRF2-13 proteinsare described below. A homologous amino acid sequence does not encodethe amino acid sequence of a human CRF2-13 polypeptide.

[0105] The nucleotide sequence determined from the cloning of the humanCRF2-13 gene allows for the generation of probes and primers designedfor use in identifying and/or cloning CRF2-13 homologues in other celltypes, e.g., from other tissues, as well as CRF2-13 homologues fromother mammals. The probe/primer typically comprises a substantiallypurified oligonucleotide. The oligonucleotide typically comprises aregion of nucleotide sequence that hybridizes under stringent conditionsto at least about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 ormore consecutive sense strand nucleotide sequence of SEQ ID NO:1; or ananti-sense strand nucleotide sequence of SEQ ID NO:1; or of a naturallyoccurring mutant of SEQ ID NO:1.

[0106] Probes based on the human CRF2-13 nucleotide sequence can be usedto detect transcripts or genomic sequences encoding the same orhomologous proteins. In various embodiments, the probe further comprisesa label group attached thereto, e.g., the label group can be aradioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor.Such probes can be used as a part of a diagnostic test kit foridentifying cells or tissue which misexpress a CRF2-13 protein, such asby measuring a level of a CRF2-13-encoding nucleic acid in a sample ofcells from a subject e.g., detecting CRF2-13 mRNA levels or determiningwhether a genomic CRF2-13 gene has been mutated or deleted.

[0107] A “polypeptide having a biologically active portion of CRF2-13”refers to polypeptides exhibiting activity similar, but not necessarilyidentical to, an activity of a polypeptide of the present invention,including mature forms, as measured in a particular biological assay,with or without dose dependency. A nucleic acid fragment encoding a“biologically active portion of CRF2-13” can be prepared by isolating aportion of SEQ ID NO:1 that encodes a polypeptide having a CRF2-13biological activity (biological activities of the CRF2-13 proteins aredescribed below), expressing the encoded portion of CRF2-13 protein(e.g., by recombinant expression in vitro) and assessing the activity ofthe encoded portion of CRF2-13. For example, a nucleic acid fragmentencoding a biologically active portion of CRF2-13 can optionally includea cytokine-binding domain. In another embodiment, a nucleic acidfragment encoding a biologically active portion of CRF2-13 includes oneor more regions.

[0108] Polymorphisms in CRF2-13 Associated Sequences

[0109] The invention also provides polymorphic forms of CRF2-13 nucleicacid sequences as well as methods of detecting polymorphic sequences inCRF2-13 sequences The polymorphic forms include genomic sequencescorresponding to exons and/or introns associated with CRF2-13. Thepolymorphisms can be provided on various isolated CRF2-13 nucleic acids.For example, the polymorphism can be provided on an isolatedpolynucleotide comprising at least 10 contiguous nucleotides of SEQ IDNO:3 that include the polymorphic sequences shown in Table 6.Alternatively, the polymorphism can be provided on an isolatedpolynucleotide comprising at least 10 nucleotides of SEQ ID NO:2 thatinclude alternative forms of the polymorphic sequences shown in Table 9.

[0110] For example, an isolated CRF2-13 polymorphic sequence can includefrom nucleotide 30957 to nucleotide 30967 of SEQ ID NO:3, provided thatposition 30962 is “A or “G”. In a second example, the isolated CRF2-13polymorphic sequence can include at least 10 contiguous nucleotides fromnucleotide 30650 to nucleotide 30660 of SEQ ID NO:3, provided thatposition 30655 is “A” or “G”. In additional examples, the isolatedCRF2-13 nucleic acid sequence includes at least 10 contiguousnucleotides from nucleotide 28739 to nucleotide 28749 of SEQ ID NO:3,wherein position 28744 is “A” or “G”; at least 10 contiguous nucleotidesfrom nucleotide 28442 to 28452 of SEQ ID NO:3, wherein position 28448 is“C” or “T”; additional examples include an isolated polynucleotidecomprising at least 10 contiguous nucleotides from nucleotide 9421 to9431 of SEQ ID NO:3, wherein position 9426 of the polynucleotide is “A”or “G”, or an isolated polynucleotide comprising at least 10 contiguousnucleotides from nucleotide 8806 to 8816 of SEQ ID NO:3, whereinposition 8811 of the polynucleotide is “C or “T”.

[0111] Alternatively, an isolated CRF2-13 polymorphic sequence caninclude from nucleotide 32954 to nucleotide 32964 of SEQ ID NO:22,provided that position 30962 is “C” or “A”. Alternatively, thepolymorphic sequence can include from nucleotide 31262 to 31272 of SEQID NO:22, provided that position 31266 is “C” or “T”; or nucleotides30955 to 20965 of SEQ ID NO:22, provided that nucleotide 30960 is “T” or“C”; or nucleotides 29043 to 29053 of SEQ ID NO:22, provided thatnucleotide 29048 is “C” or “T”; or nucleotides 28748 to 28758 of SEQ IDNO:22, provided that nucleotide 28753 is “G” or “A”; or nucleotides23825 to 23835 of SEQ ID NO:22, provided that nucleotide 23830 is “G” or“A”.

[0112] In additional embodiments, the polymorphic nucleic acid includesat least 15, 20, 25, 50, 75, 100, 150, 250, 500, 750, or 1000 or morecontiguous nucleotides from SEQ ID NO:3. In some embodiments, thepolymorphic nucleotide sequence is 10-1000 nucleotides in length. Forexample, the polymorphic nucleotide sequence can be 20-750 nucleotides,50-625 nucleotides, 75-500 nucleotides, 100-250 nucleotides in length.

[0113] Individuals carrying polymorphic alleles of the invention may bedetected at either the DNA, the RNA, or the protein level using avariety of techniques that are well known in the art. Strategies foridentification and detection are described in e.g., EP 730,663, EP717,113, and PCT US97/02102. The present methods usually employpre-characterized polymorphisms. That is, the genotyping location andnature of polymorphic forms present at a site have already beendetermined. The availability of this information allows sets of probesto be designed for specific identification of the known polymorphicforms.

[0114] Many of the methods described below require amplification of DNAfrom target samples. This can be accomplished by e.g., PCR. (1989), B.for detecting polymorphisms. See generally PCR Technology: Principlesand Applications for DNA Amplification (ed. H. A. Erlich, Freeman Press,NY, N.Y., 1992); PCR Protocols: A Guide to Methods and Applications(eds. Innis, et al., Academic Press, San Diego, Calif., 1990); Mattilaet al., Nucleic Acids Res. 19, 4967 (1991); Eckert et al., PCR Methodsand Applications 1, 17 (1991); PCR (eds. McPherson et al., IRL Press,Oxford); and U.S. Pat. No. 4,683,202.

[0115] The genomic DNA used for the diagnosis may be obtained from anynucleated cells of the body, such as those present in peripheral blood,urine, saliva, buccal samples, surgical specimen, and autopsy specimens.The DNA may be used directly or may be amplified enzymatically in vitrothrough use of PCR (Saiki et al. Science 239:487-491 (1988)) or other invitro amplification methods such as the ligase chain reaction (LCR) (Wuand Wallace Genomics 4:560-569 (1989)), strand displacementamplification (SDA) (Walker et al. Proc. Natl. Acad. Sci. U.S.A,89:392-396 (1992)), self-sustained sequence replication (3SR) (Fahy etal. PCR Methods P&J& 1:25-33 (1992)), prior to mutation analysis.

[0116] The detection of polymorphisms in specific DNA sequences, can beaccomplished by a variety of methods including, but not limited to,restriction-fragment-length-polymorphism detection based onallele-specific restriction-endonuclease cleavage (Kan and Dozy Lancetii:910-912 (1978)), hybridization with allele-specific oligonucleotideprobes (Wallace et al. Nucl. Acids Res. 6:3543-3557 (1978)), includingimmobilized oligonucleotides (Saiki et al. Proc. Natl. Acad. SCI. USA,86:6230-6234 (1969)) or oligonucleotide arrays (Maskos and SouthernNucl. Acids Res 21:2269-2270 (1993)), allele-specific PCR (Newton et al.Nucl Acids Res 17:2503-2516 (1989)), mismatch-repair detection (MRD)(Faham and Cox Genome Res 5:474-482 (1995)), binding of MutS protein(Wagner et al. Nucl Acids Res 23:3944-3948 (1995), denaturing-gradientgel electrophoresis (DGGE) (Fisher and Lerman et al. Proc. Natl. Acad.Sci. U.S.A. 80:1579-1583 (1983)),single-strand-conformation-polymorphism detection (Orita et al. Genomics5:874-879 (1983)), RNAase cleavage at mismatched base-pairs (Myers etal. Science 230:1242 (1985)), chemical (Cotton et al. Proc. Natl. w Sci.U.S.A, 8Z4397-4401 (1988)) or enzymatic (Youil et al. Proc. Natl. Acad.Sci. U.S.A. 92:87-91 (1995)) cleavage of heteroduplex DNA, methods basedon allele specific primer_extension (Syvanen et al. Genomics 8:684-692(1990)), genetic bit analysis (GBA) (Nikiforov et al. &&I Acids22:4167-4175 (1994)), the oligonucleotide-ligation assay (OLA)(Landegren et al. Science 241:1077 (1988)), the allele-specific ligationchain reaction (LCR) (Barrany Proc. Natl. Acad. Sci. U.S.A. 88:189-193(1991)), gap-LCR (Abravaya et al. Nucl Acids Res 23:675-682 (1995)),radioactive and/or fluorescent DNA sequencing using standard procedureswell known in the art, and peptide nucleic acid (PNA) assays (Orum etal., Nucl. Acids Res, 21:5332-5356 (1993); Thiede et al., Nucl. AcidsRes. 24:983-984 (1996)).

[0117] CRF2-13 Variants

[0118] The invention further encompasses nucleic acid molecules thatdiffer from the nucleotide sequences shown in SEQ ID NO:1 due to thedegeneracy of the genetic code. These nucleic acids thus encode the sameCRF2-13 protein as that encoded by the nucleotide sequence shown in SEQID NO:1, e.g., the polypeptide of SEQ ID NO:2. In another embodiment, anisolated nucleic acid molecule of the invention has a nucleotidesequence encoding a protein having an amino acid sequence shown in SEQID NO:2.

[0119] In addition to the human CRF2-13 nucleotide sequence shown in SEQID NO:1, it will be appreciated by those skilled in the art that DNAsequence polymorphisms that lead to changes in the amino acid sequencesof CRF2-13 may exist within a population (e.g., the human population).Such genetic polymorphism in the CRF2-13 gene may exist amongindividuals within a population due to natural allelic variation. Asused herein, the terms “gene” and “recombinant gene” refer to nucleicacid molecules comprising an open reading frame encoding a CRF2-13protein, preferably a mammalian CRF2-13 protein. Such natural allelicvariations can typically result in 1-5% variance in the nucleotidesequence of the CRF2-13 gene. Any and all such nucleotide variations andresulting amino acid polymorphisms in CRF2-13 that are the result ofnatural allelic variation and that do not alter the functional activityof CRF2-13 are intended to be within the scope of the invention.

[0120] Moreover, nucleic acid molecules encoding CRF2-13 proteins fromother species, and thus that have a nucleotide sequence that differsfrom the human sequence of SEQ ID NO:1 are intended to be within thescope of the invention. Nucleic acid molecules corresponding to naturalallelic variants and homologues of the CRF2-13 cDNAs of the inventioncan be isolated based on their homology to the human CRF2-13 nucleicacids disclosed herein using the human cDNAs, or a portion thereof, as ahybridization probe according to standard hybridization techniques understringent hybridization conditions. For example, a soluble human CRF2-13cDNA can be isolated based on its homology to human membrane-boundCRF2-13. Likewise, a membrane-bound human CRF2-13 cDNA can be isolatedbased on its homology to soluble human CRF2-13.

[0121] Accordingly, in another embodiment, an isolated nucleic acidmolecule of the invention is at least 6 nucleotides in length andhybridizes under stringent conditions to the nucleic acid moleculecomprising the nucleotide sequence of SEQ ID NO:1. In anotherembodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500 or750 nucleotides in length. In another embodiment, an isolated nucleicacid molecule of the invention hybridizes to the coding region. As usedherein, the term “hybridizes under stringent conditions” is intended todescribe conditions for hybridization and washing under which nucleotidesequences at least 60% homologous to each other typically remainhybridized to each other.

[0122] Homologs (i.e., nucleic acids encoding CRF2-13 proteins derivedfrom species other than human) or other related sequences (e.g.,paralogs) can be obtained by low, moderate or high stringencyhybridization with all or a portion of the particular human sequence asa probe using methods well known in the art for nucleic acidhybridization and cloning.

[0123] As used herein, the phrase “stringent hybridization conditions”refers to conditions under which a probe, primer or oligonucleotide willhybridize to its target sequence, but to no other sequences. Stringentconditions are sequence-dependent and will be different in differentcircumstances. Longer sequences hybridize specifically at highertemperatures than shorter sequences. Generally, stringent conditions areselected to be about 5° C. lower than the thermal melting point (T_(m))for the specific sequence at a defined ionic strength and pH. The T_(m)is the temperature (under defined ionic strength, pH and nucleic acidconcentration) at which 50% of the probes complementary to the targetsequence hybridize to the target sequence at equilibrium. Since thetarget sequences are generally present at excess, at Tm, 50% of theprobes are occupied at equilibrium. Typically, stringent conditions willbe those in which the salt concentration is less than about 1.0 M sodiumion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0to 8.3 and the temperature is at least about 30° C. for short probes,primers or oligonucleotides (e.g, 10 nt to 50 nt) and at least about 60°C. for longer probes, primers and oligonucleotides. Stringent conditionsmay also be achieved with the addition of destabilizing agents, such asformamide.

[0124] Stringent conditions are known to those skilled in the art andcan be found in CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley &Sons, N.Y. (1989), 6.3.1-6.3.6. Preferably, the conditions are such thatsequences at least about 65%, 70%, 75%, 85%, 90%, 95%, 98%, or 99%homologous to each other typically remain hybridized to each other. Anon-limiting example of stringent hybridization conditions ishybridization in a high salt buffer comprising 6×SSC, 50 mM Tris-HCl (pH7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/mldenatured salmon sperm DNA at 65° C. This hybridization is followed byone or more washes in 0.2×SSC, 0.01% BSA at 50° C. An isolated nucleicacid molecule of the invention that hybridizes under stringentconditions to the sequence of SEQ ID NO:1 corresponds to a naturallyoccurring nucleic acid molecule. As used herein, a “naturally-occurring”nucleic acid molecule refers to an RNA or DNA molecule having anucleotide sequence that occurs in nature (e.g., encodes a naturalprotein).

[0125] In a second embodiment, a nucleic acid sequence that ishybridizable to the nucleic acid molecule comprising the nucleotidesequence of SEQ ID NO:1, or fragments, analogs or derivatives thereof,under conditions of moderate stringency is provided. A non-limitingexample of moderate stringency hybridization conditions arehybridization in 6×SSC, 5× Denhardt's solution, 0.5% SDS and 100 mg/mldenatured salmon sperm DNA at 55° C., followed by one or more washes in1×SSC, 0.1% SDS at 37° C. Other conditions of moderate stringency thatmay be used are well known in the art. See, e.g., Ausubel et al. (eds.),1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, andKriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL,Stockton Press, NY.

[0126] In a third embodiment, a nucleic acid that is hybridizable to thenucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1,or fragments, analogs or derivatives thereof, under conditions of lowstringency, is provided. A non-limiting example of low stringencyhybridization conditions are hybridization in 35% formamide, 5×SSC, 50mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100mg/ml denatured salmon sperm DNA, 10% (wt/vol) dextran sulfate at 40°C., followed by one or more washes in 2×SSC, 25 mM Tris-HCl (pH 7.4), 5mM EDTA, and 0.1% SDS at 50° C. Other conditions of low stringency thatmay be used are well known in the art (e.g., as employed forcross-species hybridizations). See, e.g., Ausubel et al. (eds.), 1993,CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, andKriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL,Stockton Press, NY; Shilo and Weinberg, 1981, Proc Natl Acad Sci USA 78:6789-6792.

[0127] Conservative Mutations

[0128] In addition to naturally-occurring allelic variants of theCRF2-13 sequence that may exist in the population, the skilled artisanwill further appreciate that changes can be introduced by mutation intothe nucleotide sequence of SEQ ID NO:1, thereby leading to changes inthe amino acid sequence of the encoded CRF2-13 protein, without alteringthe functional ability of the CRF2-13 protein. For example, nucleotidesubstitutions leading to amino acid substitutions at “non-essential”amino acid residues can be made in the sequence of SEQ ID NO:1. A“non-essential” amino acid residue is a residue that can be altered fromthe wild-type sequence of CRF2-13 without altering the biologicalactivity, whereas an “essential” amino acid residue is required forbiological activity. For example, amino acid residues that are conservedamong the CRF2-13 proteins of the present invention, are predicted to beparticularly unamenable to alteration.

[0129] Another aspect of the invention pertains to nucleic acidmolecules encoding CRF2-13 proteins that contain changes in amino acidresidues that are not essential for activity. Such CRF2-13 proteinsdiffer in amino acid sequence from SEQ ID NO:2, yet retain biologicalactivity. In one embodiment, the isolated nucleic acid moleculecomprises a nucleotide sequence encoding a protein, wherein the proteincomprises an amino acid sequence at least about 75% homologous to theamino acid sequence of SEQ ID NO:2. Preferably, the protein encoded bythe nucleic acid is at least about 80% homologous to SEQ ID NO:2, morepreferably at least about 90%, 95%, 98%, and most preferably at leastabout 99% homologous to SEQ ID NO:2.

[0130] An isolated nucleic acid molecule encoding a CRF2-13 proteinhomologous to the protein of SEQ ID NO:2 can be created by introducingone or more nucleotide substitutions, additions or deletions into thenucleotide sequence of SEQ ID NO:1, such that one or more amino acidsubstitutions, additions or deletions are introduced into the encodedprotein.

[0131] Mutations can be introduced into the nucleotide sequence of SEQID NO:1 by standard techniques, such as site-directed mutagenesis andPCR-mediated mutagenesis. Preferably, conservative amino acidsubstitutions are made at one or more predicted non-essential amino acidresidues. A “conservative amino acid substitution” is one in which theamino acid residue is replaced with an amino acid residue having asimilar side chain. Families of amino acid residues having similar sidechains have been defined in the art. These families include amino acidswith basic side chains (e.g., lysine, arginine, histidine), acidic sidechains (e.g., aspartic acid, glutamic acid), uncharged polar side chains(e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine,cysteine), nonpolar side chains (e.g., alanine, valine, leucine,isoleucine, proline, phenylalanine, methionine, tryptophan),beta-branched side chains (e.g., threonine, valine, isoleucine) andaromatic side chains (e.g., tyrosine, phenylalanine, tryptophan,histidine). Thus, a predicted nonessential amino acid residue in CRF2-13is replaced with another amino acid residue from the same side chainfamily. Alternatively, in another embodiment, mutations can beintroduced randomly along all or part of a CRF2-13 coding sequence, suchas by saturation mutagenesis, and the resultant mutants can be screenedfor CRF2-13 biological activity to identify mutants that retainactivity. Following mutagenesis of SEQ ID NO:1 the encoded protein canbe expressed by any recombinant technology known in the art and theactivity of the protein can be determined.

[0132] In one embodiment, a mutant CRF2-13 protein can be assayed for(1) the ability to form protein:protein interactions with other CRF2-13proteins, other cell-surface proteins, or biologically active portionsthereof, (2) complex formation between a mutant CRF2-13 protein and aCRF2-13 receptor; (3) the ability of a mutant CRF2-13 protein to bind toan intracellular target protein or biologically active portion thereof;(e.g., avidin proteins); (4) the ability to bind CRF2-13 protein; or (5)the ability to specifically bind an anti-CRF2-13 protein antibody.

[0133] Antisense CRF2-13 Nucleic Acids

[0134] Another aspect of the invention pertains to isolated antisensenucleic acid molecules that are hybridizable to or complementary to thenucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1,or fragments, analogs or derivatives thereof. An “antisense” nucleicacid comprises a nucleotide sequence that is complementary to a “sense”nucleic acid encoding a protein, e.g., complementary to the codingstrand of a double-stranded cDNA molecule or complementary to an mRNAsequence. In specific aspects, antisense nucleic acid molecules areprovided that comprise a sequence complementary to at least about 10,25, 50, 100, 250 or 500 nucleotides or an entire CRF2-13 coding strand,or to only a portion thereof. Nucleic acid molecules encoding fragments,homologs, derivatives and analogs of a CRF2-13 protein of SEQ ID NO:2,or antisense nucleic acids complementary to a CRF2-13 nucleic acidsequence of SEQ ID NO:1 are additionally provided.

[0135] In one embodiment, an antisense nucleic acid molecule isantisense to a “coding region” of the coding strand of a nucleotidesequence encoding CRF2-3. The term “coding region” refers to the regionof the nucleotide sequence comprising codons which are translated intoamino acid residues (e.g., the protein coding region of human CRF2-13corresponds to SEQ ID NO:2). In another embodiment, the antisensenucleic acid molecule is antisense to a “noncoding region” of the codingstrand of a nucleotide sequence encoding CRF2-13. The term “noncodingregion” refers to 5′ and 3′ sequences which flank the coding region thatare not translated into amino acids (i.e., also referred to as 5′ and 3′untranslated regions).

[0136] Given the coding strand sequences encoding CRF2-13 disclosedherein (e.g., SEQ ID NO:1), antisense nucleic acids of the invention canbe designed according to the rules of Watson and Crick or Hoogsteen basepairing. The antisense nucleic acid molecule can be complementary to theentire coding region of CRF2-13 mRNA, but more preferably is anoligonucleotide that is antisense to only a portion of the coding ornoncoding region of CRF2-13 mRNA. For example, the antisenseoligonucleotide can be complementary to the region surrounding thetranslation start site of CRF2-13 mRNA. An antisense oligonucleotide canbe, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50nucleotides in length. An antisense nucleic acid of the invention can beconstructed using chemical synthesis or enzymatic ligation reactionsusing procedures known in the art. For example, an antisense nucleicacid (e.g., an antisense oligonucleotide) can be chemically synthesizedusing naturally occurring nucleotides or variously modified nucleotidesdesigned to increase the biological stability of the molecules or toincrease the physical stability of the duplex formed between theantisense and sense nucleic acids, e.g., phosphorothioate derivativesand acridine substituted nucleotides can be used.

[0137] Examples of modified nucleotides that can be used to generate theantisense nucleic acid include: 5-fluorouracil, 5-bromouracil,5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine,5-(carboxyhydroxylmethyl) uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N-6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w,and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can beproduced biologically using an expression vector into which a nucleicacid has been subcloned in an antisense orientation (i.e., RNAtranscribed from the inserted nucleic acid will be of an antisenseorientation to a target nucleic acid of interest, described further inthe following subsection).

[0138] The antisense nucleic acid molecules of the invention aretypically administered to a subject or generated in situ such that theyhybridize with or bind to cellular mRNA and/or genomic DNA encoding aCRF2-13 protein to thereby inhibit expression of the protein, e.g., byinhibiting transcription and/or translation. The hybridization can be byconventional nucleotide complementarity to form a stable duplex, or, forexample, in the case of an antisense nucleic acid molecule that binds toDNA duplexes, through specific interactions in the major groove of thedouble helix. An example of a route of administration of antisensenucleic acid molecules of the invention includes direct injection at atissue site. Alternatively, antisense nucleic acid molecules can bemodified to target selected cells and then administered systemically.For example, for systemic administration, antisense molecules can bemodified such that they specifically bind to receptors or antigensexpressed on a selected cell surface, e.g., by linking the antisensenucleic acid molecules to peptides or antibodies that bind to cellsurface receptors or antigens. The antisense nucleic acid molecules canalso be delivered to cells using the vectors described herein. Toachieve sufficient intracellular concentrations of antisense molecules,vector constructs in which the antisense nucleic acid molecule is placedunder the control of a strong pol II or pol III promoter are preferred.

[0139] In yet another embodiment, the antisense nucleic acid molecule ofthe invention is an α-anomeric nucleic acid molecule. An α-anomericnucleic acid molecule forms specific double-stranded hybrids withcomplementary RNA in which, contrary to the usual β-units, the strandsrun parallel to each other (Gaultier et al. (1987) Nucleic Acids Res 15:6625-6641). The antisense nucleic acid molecule can also comprise a2′-o-methylribonucleotide (Inoue et al. (1987) Nucleic Acids Res 15:6131-6148) or a chimeric RNA—DNA analogue (Inoue et al. (1987) FEBS Lett215: 327-330).

[0140] Such modifications include, by way of nonlimiting example,modified bases, and nucleic acids whose sugar phosphate backbones aremodified or derivatized. These modifications are carried out at least inpart to enhance the chemical stability of the modified nucleic acid,such that they may be used, for example, as antisense binding nucleicacids in therapeutic applications in a subject.

[0141] CRF2-13 Ribozymes and PNA Moieties

[0142] In still another embodiment, an antisense nucleic acid of theinvention is a ribozyme. Ribozymes are catalytic RNA molecules withribonuclease activity that are capable of cleaving a single-strandednucleic acid, such as a mRNA, to which they have a complementary region.Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff andGerlach (1988) Nature 334:585-591)) can be used to catalytically cleaveCRF2-13 mRNA transcripts to thereby inhibit translation of CRF2-13 mRNA.A ribozyme having specificity for a CRF2-13-encoding nucleic acid can bedesigned based upon the nucleotide sequence of a CRF2-13 DNA disclosedherein (i.e., SEQ ID NO:1). For example, a derivative of a TetrahymenaL-19 IVS RNA can be constructed in which the nucleotide sequence of theactive site is complementary to the nucleotide sequence to be cleaved ina CRF2-13-encoding mRNA. See, e.g., Cech et al. U.S. Pat. No. 4,987,071;and Cech et al. U.S. Pat. No. 5,116,742. Alternatively, CRF2-13 mRNA canbe used to select a catalytic RNA having a specific ribonucleaseactivity from a pool of RNA molecules. See, e.g., Bartel et al., (1993)Science 261:1411-1418.

[0143] Alternatively, CRF2-13 gene expression can be inhibited bytargeting nucleotide sequences complementary to the regulatory region ofthe CRF2-13 (e.g., the CRF2-13 promoter and/or enhancers) to form triplehelical structures that prevent transcription of the CRF2-13 gene intarget cells. See generally, Helene. (1991) Anticancer Drug Des. 6:569-84; Helene. et al. (1992) Ann. N.Y. Acad. Sci. 660:27-36; and Maher(1992) Bioassays 14: 807-15.

[0144] In various embodiments, the nucleic acids of CRF2-13 can bemodified at the base moiety, sugar moiety or phosphate backbone toimprove, e.g., the stability, hybridization, or solubility of themolecule. For example, the deoxyribose phosphate backbone of the nucleicacids can be modified to generate peptide nucleic acids (see Hyrup etal. (1996) Bioorg Med Chem 4: 5-23). As used herein, the terms “peptidenucleic acids” or “PNAs” refer to nucleic acid mimics, e.g., DNA mimics,in which the deoxyribose phosphate backbone is replaced by apseudopeptide backbone and only the four natural nucleobases areretained. The neutral backbone of PNAs has been shown to allow forspecific hybridization to DNA and RNA under conditions of low ionicstrength. The synthesis of PNA oligomers can be performed using standardsolid phase peptide synthesis protocols as described in Hyrup et al.(1996) above; Perry-O'Keefe et al. (1996) PNAS 93: 14670-675.

[0145] PNAs of CRF2-13 can be used in therapeutic and diagnosticapplications. For example, PNAs can be used as antisense or antigeneagents for sequence-specific modulation of gene expression by, e.g.,inducing transcription or translation arrest or inhibiting replication.PNAs of CRF2-13 can also be used, e.g., in the analysis of single basepair mutations in a gene by, e.g., PNA directed PCR clamping; asartificial restriction enzymes when used in combination with otherenzymes, e.g, S1 nucleases (Hyrup B. (1996) above); or as probes orprimers for DNA sequence and hybridization (Hyrup et al. (1996), above;Perry-O'Keefe (1996), above).

[0146] In another embodiment, PNAs of CRF2-13 can be modified, e.g., toenhance their stability or cellular uptake, by attaching lipophilic orother helper groups to PNA, by the formation of PNA-DNA chimeras, or bythe use of liposomes or other techniques of drug delivery known in theart. For example, PNA-DNA chimeras of CRF2-13 can be generated that maycombine the advantageous properties of PNA and DNA. Such chimeras allowDNA recognition enzymes, e.g., RNase H and DNA polymerases, to interactwith the DNA portion while the PNA portion would provide high bindingaffinity and specificity. PNA-DNA chimeras can be linked using linkersof appropriate lengths selected in terms of base stacking, number ofbonds between the nucleobases, and orientation (Hyrup (1996) above). Thesynthesis of PNA-DNA chimeras can be performed as described in Hyrup(1996) above and Finn et al. (1996) Nucl Acids Res 24: 3357-63. Forexample, a DNA chain can be synthesized on a solid support usingstandard phosphoramidite coupling chemistry, and modified nucleosideanalogs, e.g., 5′-(4-methoxytrityl) amino-5′-deoxy-thymidinephosphoramidite, can be used between the PNA and the 5′ end of DNA (Maget al. (1989) Nucl Acid Res 17: 5973-88). PNA monomers are then coupledin a stepwise manner to produce a chimeric molecule with a 5′ PNAsegment and a 3′ DNA segment (Finn et al. (1996) above). Alternatively,chimeric molecules can be synthesized with a 5′ DNA segment and a 3′ PNAsegment. See, Petersen et al. (1975) Bioorg Med Chem Lett5: 1119-11124.

[0147] In other embodiments, the oligonucleotide may include otherappended groups such as peptides (e.g., for targeting host cellreceptors in vivo), or agents facilitating transport across the cellmembrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad. Sci.U.S.A. 86:6553-6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci.84:648-652; PCT Publication No. WO88/09810) or the blood-brain barrier(see, e.g., PCT Publication No. WO89/10134). In addition,oligonucleotides can be modified with hybridization triggered cleavageagents (See, e.g., Krol et al., 1988, BioTechniques 6:958-976) orintercalating agents. (See, e.g., Zon, 1988, Pharm. Res. 5: 539-549). Tothis end, the oligonucleotide may be conjugated to another molecule,e.g., a peptide, a hybridization triggered cross-linking agent, atransport agent, a hybridization-triggered cleavage agent, etc.

[0148] CRF2-13 Polypeptides

[0149] A CRF2-13 polypeptide of the invention includes the CRF2-13-likeprotein whose sequence is provided in SEQ ID NO:2. In some embodiments,a CRF2-13 polypeptide includes amino acid sequences 21-520, amino acids21-230 of SEQ ID NO:2, amino acids 21-246 of SEQ ID NO:2, amino acids231-520 of SEQ ID NO:2, amino acids 247-520 of SEQ ID NO:2. Theinvention also includes a mutant or variant form of the disclosedCRF2-13 polypeptide, or of any of the fragments of the herein disclosedCRF2-13 polypeptide sequences.

[0150] Thus, a CRF2-13 polypeptide includes one in which any residuesmay be changed from the corresponding residue shown in SEQ ID NO:2 whilestill encoding a protein that maintains its CRF2-13-like activities andphysiological functions, or a functional fragment thereof. In someembodiments, up to 20% or more of the residues may be so changed in themutant or variant protein. In some embodiments, the CRF2-13 polypeptideaccording to the invention is a mature polypeptide.

[0151] In general, a CRF2-13-like variant that preserves CRF2-13-likefunction includes any variant in which residues at a particular positionin the sequence have been substituted by other amino acids, and furtherinclude the possibility of inserting an additional residue or residuesbetween two residues of the parent protein as well as the possibility ofdeleting one or more residues from the parent sequence. Any amino acidsubstitution, insertion, or deletion is encompassed by the invention. Infavorable circumstances, the substitution is a conservative substitutionas defined above.

[0152] One aspect of the invention pertains to isolated CRF2-13proteins, and biologically active portions thereof, or derivatives,fragments, analogs or homologs thereof. Also provided are polypeptidefragments suitable for use as immunogens to raise anti-CRF2-13antibodies. In one embodiment, native CRF2-13 proteins can be isolatedfrom cells or tissue sources by an appropriate purification scheme usingstandard protein purification techniques. In another embodiment, CRF2-13proteins are produced by recombinant DNA techniques. Alternative torecombinant expression, a CRF2-13 protein or polypeptide can besynthesized chemically using standard peptide synthesis techniques.

[0153] A “purified” protein or biologically active portion thereof issubstantially free of cellular material or other contaminating proteinsfrom the cell or tissue source from which the CRF2-13 protein isderived, or substantially free from chemical precursors or otherchemicals when chemically synthesized. The language “substantially freeof cellular material” includes preparations of CRF2-13 protein in whichthe protein is separated from cellular components of the cells fromwhich it is isolated or recombinantly produced. In one embodiment, thelanguage “substantially free of cellular material” includes preparationsof CRF2-13 protein having less than about 30% (by dry weight) ofnon-CRF2-13 protein (also referred to herein as a “contaminatingprotein”), more preferably less than about 20% of non-CRF2-13 protein,still more preferably less than about 10% of non-CRF2-13 protein, andmost preferably less than about 5% non-CRF2-13 protein. When the CRF2-13protein or biologically active portion thereof is recombinantlyproduced, it is also preferably substantially free of culture medium,i.e., culture medium represents less than about 20%, more preferablyless than about 10%, and most preferably less than about 5% of thevolume of the protein preparation.

[0154] The language “substantially free of chemical precursors or otherchemicals” includes preparations of CRF2-13 protein in which the proteinis separated from chemical precursors or other chemicals that areinvolved in the synthesis of the protein. In one embodiment, thelanguage “substantially free of chemical precursors or other chemicals”includes preparations of CRF2-13 protein having less than about 30% (bydry weight) of chemical precursors or non-CRF2-13 chemicals, morepreferably less than about 20% chemical precursors or non-CRF2-13chemicals, still more preferably less than about 10% chemical precursorsor non-CRF2-13 chemicals, and most preferably less than about 5%chemical precursors or non-CRF2-13 chemicals.

[0155] Biologically active portions of a CRF2-13 protein includepeptides comprising amino acid sequences sufficiently homologous to orderived from the amino acid sequence of the CRF2-13 protein, e.g., theamino acid sequence shown in SEQ ID NO:2 that include fewer amino acidsthan the full length CRF2-13 proteins, and exhibit at least one activityof a CRF2-13 protein. Typically, biologically active portions comprise adomain or motif with at least one activity of the CRF2-13 protein. Abiologically active portion of a CRF2-13 protein can be a polypeptidewhich is, for example, 10, 25, 50, 100 or more amino acids in length.

[0156] A biologically active portion of a CRF2-13 protein of the presentinvention may contain at least one of the above-identified domainsconserved between the CRF2-13 proteins. Moreover, other biologicallyactive portions, in which other regions of the protein are deleted, canbe prepared by recombinant techniques and evaluated for one or more ofthe functional activities of a native CRF2-13 protein.

[0157] In an embodiment, the CRF2-13 protein has an amino acid sequenceshown in SEQ ID NO:2. In other embodiments, the CRF2-13 protein issubstantially homologous to SEQ ID NO:2 and retains the functionalactivity of the protein of SEQ ID NO:2, yet differs in amino acidsequence due to natural allelic variation or mutagenesis, as describedin detail below. Accordingly, in another embodiment, the CRF2-13 proteinis a protein that comprises an amino acid sequence at least about 45%homologous to the amino acid sequence of SEQ ID NO:2 and retains thefunctional activity of the CRF2-13 proteins of SEQ ID NO:2.

[0158] Determining Homology Between Two or More Sequence

[0159] To determine the percent homology of two amino acid sequences orof two nucleic acids, the sequences are aligned for optimal comparisonpurposes (e.g., gaps can be introduced in either of the sequences beingcompared for optimal alignment between the sequences). The amino acidresidues or nucleotides at corresponding amino acid positions ornucleotide positions are then compared. When a position in the firstsequence is occupied by the same amino acid residue or nucleotide as thecorresponding position in the second sequence, then the molecules arehomologous at that position (i.e., as used herein amino acid or nucleicacid “homology” is equivalent to amino acid or nucleic acid “identity”).

[0160] The nucleic acid sequence homology may be determined as thedegree of identity between two sequences. The homology may be determinedusing computer programs known in the art, such as GAP software providedin the GCG program package. See, Needleman and Wunsch 1970 J Mol Biol48: 443-453. Using GCG GAP software with the following settings fornucleic acid sequence comparison: GAP creation penalty of 5.0 and GAPextension penalty of 0.3, the coding region of the analogous nucleicacid sequences referred to above exhibits a degree of identitypreferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, withthe CDS (encoding) part of the DNA sequence shown in SEQ ID NO:1.

[0161] The term “sequence identity” refers to the degree to which twopolynucleotide or polypeptide sequences are identical on aresidue-by-residue basis over a particular region of comparison. Theterm “percentage of sequence identity” is calculated by comparing twooptimally aligned sequences over that region of comparison, determiningthe number of positions at which the identical nucleic acid base (e.g.,A, T, C, G, U, or I, in the case of nucleic acids) occurs in bothsequences to yield the number of matched positions, dividing the numberof matched positions by the total number of positions in the region ofcomparison (i.e., the window size), and multiplying the result by 100 toyield the percentage of sequence identity. The term “substantialidentity” as used herein denotes a characteristic of a polynucleotidesequence, wherein the polynucleotide comprises a sequence that has atleast 80 percent sequence identity, preferably at least 85 percentidentity and often 90 to 95 percent sequence identity, more usually atleast 99 percent sequence identity as compared to a reference sequenceover a comparison region. The term “percentage of positive residues” iscalculated by comparing two optimally aligned sequences over that regionof comparison, determining the number of positions at which theidentical and conservative amino acid substitutions, as defined above,occur in both sequences to yield the number of matched positions,dividing the number of matched positions by the total number ofpositions in the region of comparison (i.e., the window size), andmultiplying the result by 100 to yield the percentage of positiveresidues.

[0162] Chimeric and Fusion Proteins

[0163] The invention also provides CRF2-13 chimeric or fusion proteins.As used herein, a CRF2-13 “chimeric protein” or “fusion protein”comprises a CRF2-13 polypeptide operatively linked to a non-CRF2-13polypeptide. An “CRF2-13 polypeptide” refers to a polypeptide having anamino acid sequence corresponding to CRF2-13, whereas a “non-CRF2-13polypeptide” refers to a polypeptide having an amino acid sequencecorresponding to a protein that is not substantially homologous to theCRF2-13 protein, e.g., a protein that is different from the CRF2-13protein and that is derived from the same or a different organism.Within a CRF2-13 fusion protein the CRF2-13 polypeptide can correspondto all or a portion of a CRF2-13 protein. An example of a CRF2-13 fusionpolypeptide is one that includes amino acids 21-230 of SEQ ID NO:2(e.g., a polypeptide that includes amino acids 1-246 or amino acids21-246 of SEQ ID NO:2). In one embodiment, a CRF2-13 fusion proteincomprises at least one biologically active portion of a CRF2-13 protein.In another embodiment, a CRF2-13 fusion protein comprises at least twobiologically active portions of a CRF2-13 protein. Within the fusionprotein, the term “operatively linked” is intended to indicate that theCRF2-13 polypeptide and the non-CRF2-13 polypeptide are fused in-frameto each other. The non-CRF2-13 polypeptide can be fused to theN-terminus or C-terminus of the CRF2-13 polypeptide.

[0164] For example, in one embodiment a CRF2-13 fusion protein comprisesa CRF2-13 polypeptide operably linked to either an extracellular domainof a second protein, i.e., non-CRF2-13 protein, or to the transmembraneand intracellular domain of a second protein, i.e., non-CRF2-13 protein.Such fusion proteins can be further utilized in screening assays forcompounds that modulate CRF2-13 activity (such assays are described indetail below).

[0165] In another embodiment, the fusion protein is a GST-CRF2-13 fusionprotein in which the CRF2-13 sequences are fused to the C-terminus ofthe GST (i.e., glutathione S-transferase) sequences. Such fusionproteins can facilitate the purification of recombinant CRF2-13.

[0166] In another embodiment, the fusion protein is aCRF2-13-immunoglobulin fusion protein in which the CRF2-13 sequencescomprising one or more domains are fused to sequences derived from amember of the immunoglobulin protein family.

[0167] The CFR2-13 fusion proteins (e.g., CRF2-13-immunoglobulin fusionproteins) of the invention can be incorporated into pharmaceuticalcompositions and administered to a subject to inhibit or augment aninteraction between a cell surface receptor and its ligand. This couldoccur either by 1) binding to and removing available ligand for thereceptor (Fe mediated scavenging of the ligand affectingbioavailability); 2) binding to the ligand and blocking its ability tobind to the cell receptor (antagonizing or neutralizing); 3) associatingwith another CRF member and thereby modulating (e.g., inhibiting) adownstream signal transduction cascade; 4) associating with either aligand or another CRF and facilitating the activity of the ligand. Byall of these mechanisms, a CRF2-13 protein may be used to modulate theinteraction between a CRF2 receptor and its cognate ligand (e.g., aninteraction between IL-10 and an IL-10 receptor and interaction betweenIL-22 and an IL-22 receptor).

[0168] Inhibition of the CRF2-13 ligand/CRF2-13 interaction can be usedtherapeutically for both the treatment of proliferative anddifferentiative disorders, e,g., cancer, modulating (e.g., promoting orinhibiting) cell survival as well as immunomodulatory disorders,autoimmunity, transplantation, and inflammation by alteration ofcyotokine and chemokine cascade mechanisms. Moreover, theCRF2-13-immunoglobulin fusion proteins of the invention can be used asimmunogens to produce anti-CRF2-13 antibodies in a subject, to purifyCRF2-13 ligands, and in screening assays to identify molecules thatinhibit the interaction of CRF2-13 with a CRF2-13 ligand.

[0169] A CRF2-13 chimeric or fusion protein of the invention can beproduced by standard recombinant DNA techniques. For example, DNAfragments coding for the different polypeptide sequences are ligatedtogether in-frame in accordance with conventional techniques, e.g., byemploying blunt-ended or stagger-ended termini for ligation, restrictionenzyme digestion to provide for appropriate termini, filling-in ofcohesive ends as appropriate, alkaline phosphatase treatment to avoidundesirable joining, and enzymatic ligation. In another embodiment, thefusion gene can be synthesized by conventional techniques includingautomated DNA synthesizers. Alternatively, PCR amplification of genefragments can be carried out using anchor primers that give rise tocomplementary overhangs between two consecutive gene fragments that cansubsequently be annealed and reamplified to generate a chimeric genesequence (see, for example, Ausubel et al. (eds.) CURRENT PROTOCOLS INMOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expressionvectors are commercially available that already encode a fusion moiety(e.g., a GST polypeptide). A CRF2-13-encoding nucleic acid can be clonedinto such an expression vector such that the fusion moiety is linkedin-frame to the CRF2-13 protein.

[0170] Polypeptide Libraries

[0171] In addition, libraries of fragments of the CRF2-13 protein codingsequence can be used to generate a variegated population of CRF2-13fragments for screening and subsequent selection of variants of aCRF2-13 protein. In one embodiment, a library of coding sequencefragments can be generated by treating a double stranded PCR fragment ofa CRF2-13 coding sequence with a nuclease under conditions whereinnicking occurs only about once per molecule, denaturing the doublestranded DNA, renaturing the DNA to form double stranded DNA that caninclude sense/antisense pairs from different nicked products, removingsingle stranded portions from reformed duplexes by treatment with S1nuclease, and ligating the resulting fragment library into an expressionvector. By this method, an expression library can be derived whichencodes N-terminal and internal fragments of various sizes of theCRF2-13 protein.

[0172] Several techniques are known in the art for screening geneproducts of combinatorial libraries made by point mutations ortruncation, and for screening cDNA libraries for gene products having aselected property. Such techniques are adaptable for rapid screening ofthe gene libraries generated by the combinatorial mutagenesis of CRF2-13proteins. The most widely used techniques, which are amenable to highthroughput analysis, for screening large gene libraries typicallyinclude cloning the gene library into replicable expression vectors,transforming appropriate cells with the resulting library of vectors,and expressing the combinatorial genes under conditions in whichdetection of a desired activity facilitates isolation of the vectorencoding the gene whose product was detected. Recursive ensemblemutagenesis (REM), a new technique that enhances the frequency offunctional mutants in the libraries, can be used in combination with thescreening assays to identify CRF2-13 variants (Arkin and Yourvan (1992)PNAS 89:7811-7815; Delgrave et al. (1993) Protein Engineering6:327-331).

[0173] CRF2-13 Antibodies

[0174] Also included in the invention are antibodies to CRF2-13proteins, or fragments of CRF2-13 proteins. The term “antibody” as usedherein refers to immunoglobulin molecules and immunologically activeportions of immunoglobulin (Ig) molecules, i.e., molecules that containan antigen binding site that specifically binds (immunoreacts with) anantigen. Such antibodies include, but are not limited to, polyclonal,monoclonal, chimeric, single chain, F_(ab), F_(ab′) and F_((ab′)2)fragments, and an F_(ab) expression library. In general, an antibodymolecule obtained from humans relates to any of the classes IgG, IgM,IgA, IgE and IgD, which differ from one another by the nature of theheavy chain present in the molecule. Certain classes have subclasses aswell, such as IgG₁, IgG₂, and others. Furthermore, in humans, the lightchain may be a kappa chain or a lambda chain. Reference herein toantibodies includes a reference to all such classes, subclasses andtypes of human antibody species.

[0175] An isolated CRF2-13-related protein of the invention may beintended to serve as an antigen, or a portion or fragment thereof, andadditionally can be used as an immunogen to generate antibodies thatimmunospecifically bind the antigen, using standard techniques forpolyclonal and monoclonal antibody preparation. The full-length proteincan be used or, alternatively, the invention provides antigenic peptidefragments of the antigen for use as immunogens. An antigenic peptidefragment comprises at least 6 amino acid residues of the amino acidsequence of the full length protein, such as an amino acid sequenceshown in SEQ ID NO:2, and encompasses an epitope thereof such that anantibody raised against the peptide forms a specific immune complex withthe full length protein or with any fragment that contains the epitope.Preferably, the antigenic peptide comprises at least 10 amino acidresidues, or at least 15 amino acid residues, or at least 20 amino acidresidues, or at least 30 amino acid residues. Preferred epitopesencompassed by the antigenic peptide are regions of the protein that arelocated on its surface; commonly these are hydrophilic regions.

[0176] In certain embodiments of the invention, at least one epitopeencompassed by the antigenic peptide is a region of CRF2-13-relatedprotein that is located on the surface of the protein, e.g., ahydrophilic region. A hydrophobicity analysis of the humanCRF2-13-related protein sequence will indicate which regions of aCRF2-13-related protein are particularly hydrophilic and, therefore, arelikely to encode surface residues useful for targeting antibodyproduction. As a means for targeting antibody production, hydropathyplots showing regions of hydrophilicity and hydrophobicity may begenerated by any method well known in the art, including, for example,the Kyte Doolittle or the Hopp Woods methods, either with or withoutFourier transformation. See, e.g., Hopp and Woods, 1981, Proc. Nat.Acad. Sci. USA 78: 3824-3828; Kyte and Doolittle 1982, J. Mol. Biol.157: 105-142, each of which is incorporated herein by reference in itsentirety. Antibodies that are specific for one or more domains within anantigenic protein, or derivatives, fragments, analogs or homologsthereof, are also provided herein.

[0177] A protein of the invention, or a derivative, fragment, analog,homolog or ortholog thereof, may be utilized as an immunogen in thegeneration of antibodies that immunospecifically bind these proteincomponents.

[0178] Various procedures known within the art may be used for theproduction of polyclonal or monoclonal antibodies directed against aprotein of the invention, or against derivatives, fragments, analogshomologs or orthologs thereof (see, for example, Antibodies: ALaboratory Manual, Harlow E, and Lane D, 1988, Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y., incorporated herein byreference). Some of these antibodies are discussed below.

[0179] Polyclonal Antibodies

[0180] For the production of polyclonal antibodies, various suitablehost animals (e.g., rabbit, goat, mouse or other mammal) may beimmunized by one or more injections with the native protein, a syntheticvariant thereof, or a derivative of the foregoing. An appropriateimmunogenic preparation can contain, for example, the naturallyoccurring immunogenic protein, a chemically synthesized polypeptiderepresenting the immunogenic protein, or a recombinantly expressedimmunogenic protein. Furthermore, the protein may be conjugated to asecond protein known to be immunogenic in the mammal being immunized.Examples of such immunogenic proteins include but are not limited tokeyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, andsoybean trypsin inhibitor. The preparation can further include anadjuvant. Various adjuvants used to increase the immunological responseinclude, but are not limited to, Freund's (complete and incomplete),mineral gels (e.g., aluminum hydroxide), surface active substances(e.g., lysolecithin, pluronic polyols, polyanions, peptides, oilemulsions, dinitrophenol, etc.), adjuvants usable in humans such asBacille Calmette-Guerin and Corynebacterium parvum, or similarimmunostimulatory agents. Additional examples of adjuvants which can beemployed include MPL-TDM adjuvant (monophosphoryl Lipid A, synthetictrehalose dicorynomycolate).

[0181] The polyclonal antibody molecules directed against theimmunogenic protein can be isolated from the mammal (e.g., from theblood) and further purified by well known techniques, such as affinitychromatography using protein A or protein G, which provide primarily theIgG fraction of immune serum. Subsequently, or alternatively, thespecific antigen which is the target of the immunoglobulin sought, or anepitope thereof, may be immobilized on a column to purify the immunespecific antibody by immunoaffinity chromatography. Purification ofimmunoglobulins is discussed, for example, by D. Wilkinson (TheScientist, published by The Scientist, Inc., Philadelphia Pa., Vol. 14,No. 8 (Apr. 17, 2000), pp. 25-28).

[0182] Monoclonal Antibodies

[0183] The term “monoclonal antibody” (MAb) or “monoclonal antibodycomposition”, as used herein, refers to a population of antibodymolecules that contain only one molecular species of antibody moleculeconsisting of a unique light chain gene product and a unique heavy chaingene product. In particular, the complementarity determining regions(CDRs) of the monoclonal antibody are identical in all the molecules ofthe population. MAbs thus contain an antigen binding site capable ofimmunoreacting with a particular epitope of the antigen characterized bya unique binding affinity for it.

[0184] Monoclonal antibodies can be prepared using hybridoma methods,such as those described by Kohler and Milstein, Nature, 256:495 (1975).In a hybridoma method, a mouse, hamster, or other appropriate hostanimal, is typically immunized with an immunizing agent to elicitlymphocytes that produce or are capable of producing antibodies thatwill specifically bind to the immunizing agent. Alternatively, thelymphocytes can be immunized in vitro.

[0185] The immunizing agent will typically include the protein antigen,a fragment thereof or a fusion protein thereof. Generally, eitherperipheral blood lymphocytes are used if cells of human origin aredesired, or spleen cells or lymph node cells are used if non-humanmammalian sources are desired. The lymphocytes are then fused with animmortalized cell line using a suitable fusing agent, such aspolyethylene glycol, to form a hybridoma cell (Goding, MonoclonalAntibodies: Principles and Practice, Academic Press, (1986) pp. 59-103).Immortalized cell lines are usually transformed mammalian cells,particularly myeloma cells of rodent, bovine and human origin. Usually,rat or mouse myeloma cell lines are employed. The hybridoma cells can becultured in a suitable culture medium that preferably contains one ormore substances that inhibit the growth or survival of the unfused,immortalized cells. For example, if the parental cells lack the enzymehypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), theculture medium for the hybridomas typically will include hypoxanthine,aminopterin, and thymidine (“HAT medium”), which substances prevent thegrowth of HGPRT-deficient cells.

[0186] Preferred immortalized cell lines are those that fuseefficiently, support stable high level expression of antibody by theselected antibody-producing cells, and are sensitive to a medium such asHAT medium. More preferred immortalized cell lines are murine myelomalines, which can be obtained, for instance, from the Salk Institute CellDistribution Center, San Diego, Calif. and the American Type CultureCollection, Manassas, Va. Human myeloma and mouse-human heteromyelomacell lines also have been described for the production of humanmonoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur etal., Monoclonal Antibody Production Techniques and Applications, MarcelDekker, Inc., New York, (1987) pp. 51-63).

[0187] The culture medium in which the hybridoma cells are cultured canthen be assayed for the presence of monoclonal antibodies directedagainst the antigen. Preferably, the binding specificity of monoclonalantibodies produced by the hybridoma cells is determined byimmunoprecipitation or by an in vitro binding assay, such asradioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA).Such techniques and assays are known in the art. The binding affinity ofthe monoclonal antibody can, for example, be determined by the Scatchardanalysis of Munson and Pollard, Anal. Biochem., 107:220 (1980).Preferably, antibodies having a high degree of specificity and a highbinding affinity for the target antigen are isolated.

[0188] After the desired hybridoma cells are identified, the clones canbe subcloned by limiting dilution procedures and grown by standardmethods. Suitable culture media for this purpose include, for example,Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively,the hybridoma cells can be grown in vivo as ascites in a mammal.

[0189] The monoclonal antibodies secreted by the subclones can beisolated or purified from the culture medium or ascites fluid byconventional immunoglobulin purification procedures such as, forexample, protein A-Sepharose, hydroxylapatite chromatography, gelelectrophoresis, dialysis, or affinity chromatography.

[0190] The monoclonal antibodies can also be made by recombinant DNAmethods, such as those described in U.S. Pat. No. 4,816,567. DNAencoding the monoclonal antibodies of the invention can be readilyisolated and sequenced using conventional procedures (e.g., by usingoligonucleotide probes that are capable of binding specifically to genesencoding the heavy and light chains of murine antibodies). The hybridomacells of the invention serve as a preferred source of such DNA. Onceisolated, the DNA can be placed into expression vectors, which are thentransfected into host cells such as simian COS cells, Chinese hamsterovary (CHO) cells, or myeloma cells that do not otherwise produceimmunoglobulin protein, to obtain the synthesis of monoclonal antibodiesin the recombinant host cells. The DNA also can be modified, forexample, by substituting the coding sequence for human heavy and lightchain constant domains in place of the homologous murine sequences (U.S.Pat. No. 4,816,567; Morrison, Nature 368 812-13 (1994)) or by covalentlyjoining to the immunoglobulin coding sequence all or part of the codingsequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulinpolypeptide can be substituted for the constant domains of an antibodyof the invention, or can be substituted for the variable domains of oneantigen-combining site of an antibody of the invention to create achimeric bivalent antibody.

[0191] Humanized Antibodies

[0192] The antibodies directed against the protein antigens of theinvention can further comprise humanized antibodies or human antibodies.These antibodies are suitable for administration to humans withoutengendering an immune response by the human against the administeredimmunoglobulin. Humanized forms of antibodies are chimericimmunoglobulins, immunoglobulin chains or fragments thereof (such as Fv,Fab, Fab′, F(ab′)₂ or other antigen-binding subsequences of antibodies)that are principally comprised of the sequence of a humanimmunoglobulin, and contain minimal sequence derived from a non-humanimmunoglobulin. Humanization can be performed following the method ofWinter and co-workers (Jones et al., Nature, 321:522-525 (1986);Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science,239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences forthe corresponding sequences of a human antibody. (See also U.S. Pat. No.5,225,539.) In some instances, Fv framework residues of the humanimmunoglobulin are replaced by corresponding non-human residues.Humanized antibodies can also comprise residues which are found neitherin the recipient antibody nor in the imported CDR or frameworksequences. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the CDR regions correspond to thoseof a non-human immunoglobulin and all or substantially all of theframework regions are those of a human immunoglobulin consensussequence. The humanized antibody optimally also will comprise at least aportion of an immunoglobulin constant region (Fc), typically that of ahuman immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; andPresta, Curr. Op. Struct. Biol., 2:593-596 (1992)).

[0193] Human Antibodies

[0194] Fully human antibodies relate to antibody molecules in whichessentially the entire sequences of both the light chain and the heavychain, including the CDRs, arise from human genes. Such antibodies aretermed “human antibodies”, or “fully human antibodies” herein. Humanmonoclonal antibodies can be prepared by the trioma technique; the humanB-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4:72) and the EBV hybridoma technique to produce human monoclonalantibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCERTHERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies maybe utilized in the practice of the present invention and may be producedby using human hybridomas (see Cote, et al., 1983. Proc Natl Acad SciUSA 80: 2026-2030) or by transforming human B-cells with Epstein BarrVirus in vitro (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES ANDCANCER THERAPY, Alan R. Liss, Inc., pp. 77-96).

[0195] In addition, human antibodies can also be produced usingadditional techniques, including phage display libraries (Hoogenboom andWinter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol.,222:581 (1991)). Similarly, human antibodies can be made by introducinghuman immunoglobulin loci into transgenic animals, e.g., mice in whichthe endogenous immunoglobulin genes have been partially or completelyinactivated. Upon challenge, human antibody production is observed,which closely resembles that seen in humans in all respects, includinggene rearrangement, assembly, and antibody repertoire. This approach isdescribed, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806;5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al.(Bio/Technology 10, 779-783 (1992)); Lonberg et al. (Nature 368 856-859(1994)); Morrison (Nature 368, 812-13 (1994)); Fishwild et al,(NatureBiotechnology 14, 845-51 (1996)); Neuberger (Nature Biotechnology 14,826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13 65-93(1995)).

[0196] Human antibodies may additionally be produced using transgenicnonhuman animals which are modified so as to produce fully humanantibodies rather than the animal's endogenous antibodies in response tochallenge by an antigen. (See PCT publication WO94/02602). Theendogenous genes encoding the heavy and light immunoglobulin chains inthe nonhuman host have been incapacitated, and active loci encodinghuman heavy and light chain immunoglobulins are inserted into the host'sgenome. The human genes are incorporated, for example, using yeastartificial chromosomes containing the requisite human DNA segments. Ananimal which provides all the desired modifications is then obtained asprogeny by crossbreeding intermediate transgenic animals containingfewer than the full complement of the modifications. The preferredembodiment of such a nonhuman animal is a mouse, and is termed theXenomouse™ as disclosed in PCT publications WO 96/33735 and WO 96/34096.This animal produces B cells which secrete fully human immunoglobulins.The antibodies can be obtained directly from the animal afterimmunization with an immunogen of interest, as, for example, apreparation of a polyclonal antibody, or alternatively from immortalizedB cells derived from the animal, such as hybridomas producing monoclonalantibodies. Additionally, the genes encoding the immunoglobulins withhuman variable regions can be recovered and expressed to obtain theantibodies directly, or can be further modified to obtain analogs ofantibodies such as, for example, single chain Fv molecules.

[0197] An example of a method of producing a nonhuman host, exemplifiedas a mouse, lacking expression of an endogenous immunoglobulin heavychain is disclosed in U.S. Pat. No. 5,939,598. It can be obtained by amethod including deleting the J segment genes from at least oneendogenous heavy chain locus in an embryonic stem cell to preventrearrangement of the locus and to prevent formation of a transcript of arearranged immunoglobulin heavy chain locus, the deletion being effectedby a targeting vector containing a gene encoding a selectable marker;and producing from the embryonic stem cell a transgenic mouse whosesomatic and germ cells contain the gene encoding the selectable marker.

[0198] A method for producing an antibody of interest, such as a humanantibody, is disclosed in U.S. Pat. No. 5,916,771. It includesintroducing an expression vector that contains a nucleotide sequenceencoding a heavy chain into one mammalian host cell in culture,introducing an expression vector containing a nucleotide sequenceencoding a light chain into another mammalian host cell, and fusing thetwo cells to form a hybrid cell. The hybrid cell expresses an antibodycontaining the heavy chain and the light chain.

[0199] In a further improvement on this procedure, a method foridentifying a clinically relevant epitope on an immunogen, and acorrelative method for selecting an antibody that bindsimmunospecifically to the relevant epitope with high affinity, aredisclosed in PCT publication WO 99/53049.

[0200] F_(ab) Fragments and Single Chain Antibodies

[0201] According to the invention, techniques can be adapted for theproduction of single-chain antibodies specific to an antigenic proteinof the invention (see e.g., U.S. Pat. No. 4,946,778). In addition,methods can be adapted for the construction of F_(ab) expressionlibraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allowrapid and effective identification of monoclonal F_(ab) fragments withthe desired specificity for a protein or derivatives, fragments, analogsor homologs thereof. Antibody fragments that contain the idiotypes to aprotein antigen may be produced by techniques known in the artincluding, but not limited to: (i) an F_((ab′)2) fragment produced bypepsin digestion of an antibody molecule; (ii) an F_(ab) fragmentgenerated by reducing the disulfide bridges of an F(ab′)₂ fragment;(iii) an F_(ab) fragment generated by the treatment of the antibodymolecule with papain and a reducing agent and (iv) F_(v) fragments.

[0202] Bispecific Antibodies

[0203] Bispecific antibodies are monoclonal, preferably human orhumanized, antibodies that have binding specificities for at least twodifferent antigens. In the present case, one of the bindingspecificities is for an antigenic protein of the invention. The secondbinding target is any other antigen, and advantageously is acell-surface protein or receptor or receptor subunit.

[0204] Methods for making bispecific antibodies are known in the art.Traditionally, the recombinant production of bispecific antibodies isbased on the co-expression of two immunoglobulin heavy-chain/light-chainpairs, where the two heavy chains have different specificities (Milsteinand Cuello, Nature, 305:537-539 (1983)). Because of the randomassortment of immunoglobulin heavy and light chains, these hybridomas(quadromas) produce a potential mixture of ten different antibodymolecules, of which only one has the correct bispecific structure. Thepurification of the correct molecule is usually accomplished by affinitychromatography steps. Similar procedures are disclosed in WO 93/08829,published May 13, 1993, and in Traunecker et al., 1991 EMBO J.,10:3655-3659.

[0205] Antibody variable domains with the desired binding specificities(antibody-antigen combining sites) can be fused to immunoglobulinconstant domain sequences. The fusion preferably is with animmunoglobulin heavy-chain constant domain, comprising at least part ofthe hinge, CH2, and CH3 regions. It is preferred to have the firstheavy-chain constant region (CH1) containing the site necessary forlight-chain binding present in at least one of the fusions. DNAsencoding the immunoglobulin heavy-chain fusions and, if desired, theimmunoglobulin light chain, are inserted into separate expressionvectors, and are co-transfected into a suitable host organism. Forfurther details of generating bispecific antibodies see, for example,Suresh et al., Methods in Enzymology, 121:210 (1986).

[0206] According to another approach described in WO 96/27011, theinterface between a pair of antibody molecules can be engineered tomaximize the percentage of heterodimers which are recovered fromrecombinant cell culture. The preferred interface comprises at least apart of the CH3 region of an antibody constant domain. In this method,one or more small amino acid side chains from the interface of the firstantibody molecule are replaced with larger side chains (e.g. tyrosine ortryptophan). Compensatory “cavities” of identical or similar size to thelarge side chain(s) are created on the interface of the second antibodymolecule by replacing large amino acid side chains with smaller ones(e.g. alanine or threonine). This provides a mechanism for increasingthe yield of the heterodimer over other unwanted end-products such ashomodimers.

[0207] Bispecific antibodies can be prepared as full length antibodiesor antibody fragments (e.g. F(ab′)₂ bispecific antibodies). Techniquesfor generating bispecific antibodies from antibody fragments have beendescribed in the literature. For example, bispecific antibodies can beprepared using chemical linkage. Brennan et al., Science 229:81 (1985)describe a procedure wherein intact antibodies are proteolyticallycleaved to generate F(ab′)₂ fragments. These fragments are reduced inthe presence of the dithiol complexing agent sodium arsenite tostabilize vicinal dithiols and prevent intermolecular disulfideformation. The Fab′ fragments generated are then converted tothionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives isthen reconverted to the Fab′-thiol by reduction with mercaptoethylamineand is mixed with an equimolar amount of the other Fab′-TNB derivativeto form the bispecific antibody. The bispecific antibodies produced canbe used as agents for the selective immobilization of enzymes.

[0208] Additionally, Fab′ fragments can be directly recovered from E.coli and chemically coupled to form bispecific antibodies. Shalaby etal., J. Exp. Med. 175:217-225 (1992) describe the production of a fullyhumanized bispecific antibody F(ab′)₂ molecule. Each Fab′ fragment wasseparately secreted from E. coli and subjected to directed chemicalcoupling in vitro to form the bispecific antibody. The bispecificantibody thus formed was able to bind to cells overexpressing the ErbB2receptor and normal human T cells, as well as trigger the lytic activityof human cytotoxic lymphocytes against human breast tumor targets.

[0209] Various techniques for making and isolating bispecific antibodyfragments directly from recombinant cell culture have also beendescribed. For example, bispecific antibodies have been produced usingleucine zippers. Kostelny et al., J. Immunol. 148(5):1547-1553 (1992).The leucine zipper peptides from the Fos and Jun proteins were linked tothe Fab′ portions of two different antibodies by gene fusion. Theantibody homodimers were reduced at the hinge region to form monomersand then re-oxidized to form the antibody heterodimers. This method canalso be utilized for the production of antibody homodimers. The“diabody” technology described by Hollinger et al., Proc. Natl. Acad.Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism formaking bispecific antibody fragments. The fragments comprise aheavy-chain variable domain (V_(H)) connected to a light-chain variabledomain (V_(L)) by a linker which is too short to allow pairing betweenthe two domains on the same chain. Accordingly, the V_(H) and V_(L)domains of one fragment are forced to pair with the complementary V_(L)and V_(H) domains of another fragment, thereby forming twoantigen-binding sites. Another strategy for making bispecific antibodyfragments by the use of single-chain Fv (sFv) dimers has also beenreported. See, Gruber et al., J. Immunol. 152:5368 (1994).

[0210] Antibodies with more than two valencies are contemplated. Forexample, trispecific antibodies can be prepared. Tutt et al., J.Immunol. 147:60 (1991).

[0211] Exemplary bispecific antibodies can bind to two differentepitopes, at least one of which originates in the protein antigen of theinvention. Alternatively, an anti-antigenic arm of an immunoglobulinmolecule can be combined with an arm which binds to a triggeringmolecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2,CD3, CD28, or B7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64),FcγRII (CD32) and FcγRIII (CD16) so as to focus cellular defensemechanisms to the cell expressing the particular antigen. Bispecificantibodies can also be used to direct cytotoxic agents to cells whichexpress a particular antigen. These antibodies possess anantigen-binding arm and an arm which binds a cytotoxic agent or aradionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Anotherbispecific antibody of interest binds the protein antigen describedherein and further binds tissue factor (TF).

[0212] Heteroconjugate Antibodies

[0213] Heteroconjugate antibodies are also within the scope of thepresent invention. Heteroconjugate antibodies are composed of twocovalently joined antibodies. Such antibodies have, for example, beenproposed to target immune system cells to unwanted cells (U.S. Pat. No.4,676,980), and for treatment of HIV infection (WO 91/00360; WO92/200373; EP 03089). It is contemplated that the antibodies can beprepared in vitro using known methods in synthetic protein chemistry,including those involving crosslinking agents. For example, immunotoxinscan be constructed using a disulfide exchange reaction or by forming athioether bond. Examples of suitable reagents for this purpose includeiminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, forexample, in U.S. Pat. No. 4,676,980.

[0214] Effector Function Engineering

[0215] It can be desirable to modify the antibody of the invention withrespect to effector function, so as to enhance, e.g., the effectivenessof the antibody in treating cancer. For example, cysteine residue(s) canbe introduced into the Fe region, thereby allowing interchain disulfidebond formation in this region. The homodimeric antibody thus generatedcan have improved internalization capability and/or increasedcomplement-mediated cell killing and antibody-dependent cellularcytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195(1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimericantibodies with enhanced anti-tumor activity can also be prepared usingheterobifunctional cross-linkers as described in Wolff et al. CancerResearch, 53: 2560-2565 (1993). Alternatively, an antibody can beengineered that has dual Fc regions and can thereby have enhancedcomplement lysis and ADCC capabilities. See Stevenson et al.,Anti-Cancer Drug Design, 3: 219-230 (1989).

[0216] Immunoconjugates

[0217] The invention also pertains to immunoconjugates comprising anantibody conjugated to a cytotoxic agent such as a chemotherapeuticagent, toxin (e.g., an enzymatically active toxin of bacterial, fungal,plant, or animal origin, or fragments thereof), or a radioactive isotope(i.e., a radioconjugate).

[0218] Chemotherapeutic agents useful in the generation of suchimmunoconjugates have been described above. Enzymatically active toxinsand fragments thereof that can be used include diphtheria A chain,nonbinding active fragments of diphtheria toxin, exotoxin A chain (fromPseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain,alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolacaamericana proteins (PAPI, PAPII, and PAP-S), momordica charantiainhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin,mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. Avariety of radionuclides are available for the production ofradioconjugated antibodies. Examples include ²¹²Bi ¹³¹I, ¹¹³In, ⁹⁰Y, and¹⁸⁶Re.

[0219] Conjugates of the antibody and cytotoxic agent are made using avariety of bifunctional protein-coupling agents such asN-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane(IT), bifunctional derivatives of imidoesters (such as dimethyladipimidate HCL), active esters (such as disuccinimidyl suberate),aldehydes (such as glutareldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such asbis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such astolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin canbe prepared as described in Vitetta et al., Science, 238: 1098 (1987).Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent forconjugation of radionucleotide to the antibody. See WO94/11026.

[0220] In another embodiment, the antibody can be conjugated to a“receptor” (such streptavidin) for utilization in tumor pretargetingwherein the antibody-receptor conjugate is administered to the patient,followed by removal of unbound conjugate from the circulation using aclearing agent and then administration of a “ligand” (e.g., avidin) thatis in turn conjugated to a cytotoxic agent.

[0221] CRF2-13 Recombinant Expression Vectors and Host Cells

[0222] Another aspect of the invention pertains to vectors, preferablyexpression vectors, containing a nucleic acid encoding a CRF2-13protein, or derivatives, fragments, analogs or homologs thereof. As usedherein, the term “vector” refers to a nucleic acid molecule capable oftransporting another nucleic acid to which it has been linked. One typeof vector is a “plasmid”, which refers to a circular double stranded DNAloop into which additional DNA segments can be ligated. Another type ofvector is a viral vector, wherein additional DNA segments can be ligatedinto the viral genome. Certain vectors are capable of autonomousreplication in a host cell into which they are introduced (e.g.,bacterial vectors having a bacterial origin of replication and episomalmammalian vectors). Other vectors (e.g., non-episomal mammalian vectors)are integrated into the genome of a host cell upon introduction into thehost cell, and thereby are replicated along with the host genome.Moreover, certain vectors are capable of directing the expression ofgenes to which they are operatively-linked. Such vectors are referred toherein as “expression vectors”. In general, expression vectors ofutility in recombinant DNA techniques are often in the form of plasmids.In the present specification, “plasmid” and “vector” can be usedinterchangeably as the plasmid is the most commonly used form of vector.However, the invention is intended to include such other forms ofexpression vectors, such as viral vectors (e.g., replication defectiveretroviruses, adenoviruses and adeno-associated viruses), which serveequivalent functions.

[0223] The recombinant expression vectors of the invention comprise anucleic acid of the invention in a form suitable for expression of thenucleic acid in a host cell, which means that the recombinant expressionvectors include one or more regulatory sequences, selected on the basisof the host cells to be used for expression, that is operatively-linkedto the nucleic acid sequence to be expressed. Within a recombinantexpression vector, “operably-linked” is intended to mean that thenucleotide sequence of interest is linked to the regulatory sequence(s)in a manner that allows for expression of the nucleotide sequence (e.g.,in an in vitro transcription/translation system or in a host cell whenthe vector is introduced into the host cell).

[0224] The term “regulatory sequence” is intended to includes promoters,enhancers and other expression control elements (e.g., polyadenylationsignals). Such regulatory sequences are described, for example, inGoeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, AcademicPress, San Diego, Calif. (1990). Regulatory sequences include those thatdirect constitutive expression of a nucleotide sequence in many types ofhost cell and those that direct expression of the nucleotide sequenceonly in certain host cells (e.g., tissue-specific regulatory sequences).It will be appreciated by those skilled in the art that the design ofthe expression vector can depend on such factors as the choice of thehost cell to be transformed, the level of expression of protein desired,etc. The expression vectors of the invention can be introduced into hostcells to thereby produce proteins or peptides, including fusion proteinsor peptides, encoded by nucleic acids as described herein (e.g., CRF2-13proteins, mutant forms of CRF2-13 proteins, fusion proteins, etc.).

[0225] The recombinant expression vectors of the invention can bedesigned for expression of CRF2-13 proteins in prokaryotic or eukaryoticcells. For example, CRF2-13 proteins can be expressed in bacterial cellssuch as Escherichia coli, insect cells (using baculovirus expressionvectors) yeast cells or mammalian cells. Suitable host cells arediscussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS INENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively,the recombinant expression vector can be transcribed and translated invitro, for example using T7 promoter regulatory sequences and T7polymerase.

[0226] Expression of proteins in prokaryotes is most often carried outin Escherichia coli with vectors containing constitutive or induciblepromoters directing the expression of either fusion or non-fusionproteins. Fusion vectors add a number of amino acids to a proteinencoded therein, usually to the amino terminus of the recombinantprotein. Such fusion vectors typically serve three purposes: (i) toincrease expression of recombinant protein; (ii) to increase thesolubility of the recombinant protein; and (iii) to aid in thepurification of the recombinant protein by acting as a ligand inaffinity purification. Often, in fusion expression vectors, aproteolytic cleavage site is introduced at the junction of the fusionmoiety and the recombinant protein to enable separation of therecombinant protein from the fusion moiety subsequent to purification ofthe fusion protein. Such enzymes, and their cognate recognitionsequences, include Factor Xa, thrombin and enterokinase. Typical fusionexpression vectors include pGEX (Pharmacia Biotech Inc; Smith andJohnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly,Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) that fuse glutathioneS-transferase (GST), maltose E binding protein, or protein A,respectively, to the target recombinant protein.

[0227] Examples of suitable inducible non-fusion E. coli expressionvectors include pTrc (Amrann et al., (1988) Gene 69:301-315) and pET 11d(Studier et al., GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185,Academic Press, San Diego, Calif. (1990) 60-89).

[0228] One strategy to maximize recombinant protein expression in E.coli is to express the protein in a host bacteria with an impairedcapacity to proteolytically cleave the recombinant protein. See, e.g.,Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185,Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is toalter the nucleic acid sequence of the nucleic acid to be inserted intoan expression vector so that the individual codons for each amino acidare those preferentially utilized in E. coli (see, e.g., Wada, et al.,1992. Nucl. Acids Res. 20: 2111-2118). Such alteration of nucleic acidsequences of the invention can be carried out by standard DNA synthesistechniques.

[0229] In another embodiment, the CRF2-13 expression vector is a yeastexpression vector. Examples of vectors for expression in yeastSaccharomyces cerivisae include pYepSec1 (Baldari, et al., 1987. EMBO J.6: 229-234), pMFa (Kurjan and Herskowitz, 1982. Cell 30: 933-943),pJRY88 (Schultz et al., 1987. Gene 54: 113-123), pYES2 (InvitrogenCorporation, San Diego, Calif.), and picZ (InVitrogen Corp, San Diego,Calif.).

[0230] Alternatively, CRF2-13 can be expressed in insect cells usingbaculovirus expression vectors. Baculovirus vectors available forexpression of proteins in cultured insect cells (e.g., SF9 cells)include the pAc series (Smith, et al., 1983. Mol. Cell. Biol. 3:2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170:31-39).

[0231] In yet another embodiment, a nucleic acid of the invention isexpressed in mammalian cells using a mammalian expression vector.Examples of mammalian expression vectors include pCDM8 (Seed, 1987.Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO J. 6: 187-195).When used in mammalian cells, the expression vector's control functionsare often provided by viral regulatory elements. For example, commonlyused promoters are derived from polyoma, adenovirus 2, cytomegalovirus,and simian virus 40. For other suitable expression systems for bothprokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 ofSambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., ColdSpring Harbor Laboratory, Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y., 1989.

[0232] In another embodiment, the recombinant mammalian expressionvector is capable of directing expression of the nucleic acidpreferentially in a particular cell type (e.g., tissue-specificregulatory elements are used to express the nucleic acid).Tissue-specific regulatory elements are known in the art. Non-limitingexamples of suitable tissue-specific promoters include the albuminpromoter (liver-specific; Pinkert, et al., 1987. Genes Dev. 1: 268-277),lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol. 43:235-275), in particular promoters of T cell receptors (Winoto andBaltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins (Banerji, etal., 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33:741-748), neuron-specific promoters (e.g., the neurofilament promoter;Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477),pancreas-specific promoters (Edlund, et al., 1985. Science 230:912-916), and mammary gland-specific promoters (e.g., milk wheypromoter; U.S. Pat. No. 4,873,316 and European Application PublicationNo. 264,166). Developmentally-regulated promoters are also encompassed,e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249:374-379) and the α-fetoprotein promoter (Campes and Tilghman, 1989.Genes Dev. 3: 537-546).

[0233] The invention further provides a recombinant expression vectorcomprising a DNA molecule of the invention cloned into the expressionvector in an antisense orientation. That is, the DNA molecule isoperatively-linked to a regulatory sequence in a manner that allows forexpression (by transcription of the DNA molecule) of an RNA moleculethat is antisense to CRF2-13 mRNA. Regulatory sequences operativelylinked to a nucleic acid cloned in the antisense orientation can bechosen that direct the continuous expression of the antisense RNAmolecule in a variety of cell types, for instance viral promoters and/orenhancers, or regulatory sequences can be chosen that directconstitutive, tissue specific or cell type specific expression ofantisense RNA. The antisense expression vector can be in the form of arecombinant plasmid, phagemid or attenuated virus in which antisensenucleic acids are produced under the control of a high efficiencyregulatory region, the activity of which can be determined by the celltype into which the vector is introduced. For a discussion of theregulation of gene expression using antisense genes see, e.g.,Weintraub, et al., “Antisense RNA as a molecular tool for geneticanalysis,” Reviews-Trends in Genetics, Vol. 1(1) 1986.

[0234] Another aspect of the invention pertains to host cells into whicha recombinant expression vector of the invention has been introduced.The terms “host cell” and “recombinant host cell” are usedinterchangeably herein. It is understood that such terms refer not onlyto the particular subject cell but also to the progeny or potentialprogeny of such a cell. Because certain modifications may occur insucceeding generations due to either mutation or environmentalinfluences, such progeny may not, in fact, be identical to the parentcell, but are still included within the scope of the term as usedherein.

[0235] A host cell can be any prokaryotic or eukaryotic cell. Forexample, CRF2-13 protein can be expressed in bacterial cells such as E.coli, insect cells, yeast or mammalian cells (such as human, Chinesehamster ovary cells (CHO) or COS cells). Other suitable host cells areknown to those skilled in the art.

[0236] Vector DNA can be introduced into prokaryotic or eukaryotic cellsvia conventional transformation or transfection techniques. As usedherein, the terms “transformation” and “transfection” are intended torefer to a variety of art-recognized techniques for introducing foreignnucleic acid (e.g., DNA) into a host cell, including calcium phosphateor calcium chloride co-precipitation, DEAE-dextran-mediatedtransfection, lipofection, or electroporation. Suitable methods fortransforming or transfecting host cells can be found in Sambrook, et al.(MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring HarborLaboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor,N.Y., 1989), and other laboratory manuals.

[0237] For stable transfection of mammalian cells, it is known that,depending upon the expression vector and transfection technique used,only a small fraction of cells may integrate the foreign DNA into theirgenome. In order to identify and select these integrants, a gene thatencodes a selectable marker (e.g., resistance to antibiotics) isgenerally introduced into the host cells along with the gene ofinterest. Various selectable markers include those that conferresistance to drugs, such as G418, hygromycin and methotrexate. Nucleicacid encoding a selectable marker can be introduced into a host cell onthe same vector as that encoding CRF2-13 or can be introduced on aseparate vector. Cells stably transfected with the introduced nucleicacid can be identified by drug selection (e.g., cells that haveincorporated the selectable marker gene will survive, while the othercells die).

[0238] A host cell of the invention, such as a prokaryotic or eukaryotichost cell in culture, can be used to produce (i.e., express) CRF2-13protein. Accordingly, the invention further provides methods forproducing CRF2-13 protein using the host cells of the invention. In oneembodiment, the method comprises culturing the host cell of invention(into which a recombinant expression vector encoding CRF2-13 protein hasbeen introduced) in a suitable medium such that CRF2-13 protein isproduced. In another embodiment, the method further comprises isolatingCRF2-13 protein from the medium or the host cell.

[0239] Transgenic CRF2-13 Animals

[0240] The host cells of the invention can also be used to producenon-human transgenic animals. For example, in one embodiment, a hostcell of the invention is a fertilized oocyte or an embryonic stem cellinto which CRF2-13 protein-coding sequences have been introduced. Suchhost cells can then be used to create non-human transgenic animals inwhich exogenous CRF2-13 sequences have been introduced into their genomeor homologous recombinant animals in which endogenous CRF2-13 sequenceshave been altered. Such animals are useful for studying the functionand/or activity of CRF2-13 protein and for identifying and/or evaluatingmodulators of CRF2-13 protein activity. As used herein, a “transgenicanimal” is a non-human animal, preferably a mammal, more preferably arodent such as a rat or mouse, in which one or more of the cells of theanimal includes a transgene. Other examples of transgenic animalsinclude non-human primates, sheep, dogs, cows, goats, chickens,amphibians, etc. A transgene is exogenous DNA that is integrated intothe genome of a cell from which a transgenic animal develops and thatremains in the genome of the mature animal, thereby directing theexpression of an encoded gene product in one or more cell types ortissues of the transgenic animal. As used herein, a “homologousrecombinant animal” is a non-human animal, preferably a mammal, morepreferably a mouse, in which an endogenous CRF2-13 gene has been alteredby homologous recombination between the endogenous gene and an exogenousDNA molecule introduced into a cell of the animal, e.g., an embryoniccell of the animal, prior to development of the animal.

[0241] A transgenic animal of the invention can be created byintroducing CRF2-13-encoding nucleic acid into the male pronuclei of afertilized oocyte (e.g., by microinjection, retroviral infection) andallowing the oocyte to develop in a pseudopregnant female foster animal.Sequences including SEQ ID NO:1 can be introduced as a transgene intothe genome of a non-human animal. Alternatively, a non-human homologueof the human CRF2-13 gene, such as a mouse CRF2-13 gene, can be isolatedbased on hybridization to the human CRF2-13 cDNA (described furthersupra) and used as a transgene. Intronic sequences and polyadenylationsignals can also be included in the transgene to increase the efficiencyof expression of the transgene. A tissue-specific regulatory sequence(s)can be operably-linked to the CRF2-13 transgene to direct expression ofCRF2-13 protein to particular cells. Methods for generating transgenicanimals via embryo manipulation and microinjection, particularly animalssuch as mice, have become conventional in the art and are described, forexample, in U.S. Pat. Nos. 4,736,866; 4,870,009; and 4,873,191; andHogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y. Similar methods are used forproduction of other transgenic animals. A transgenic founder animal canbe identified based upon the presence of the CRF2-13 transgene in itsgenome and/or expression of CRF2-13 mRNA in tissues or cells of theanimals. A transgenic founder animal can then be used to breedadditional animals carrying the transgene. Moreover, transgenic animalscarrying a transgene-encoding CRF2-13 protein can further be bred toother transgenic animals carrying other transgenes.

[0242] To create a homologous recombinant animal, a vector is preparedwhich contains at least a portion of a CRF2-13 gene into which adeletion, addition or substitution has been introduced to thereby alter,e.g., functionally disrupt, the CRF2-13 gene. The CRF2-13 gene can be ahuman gene (e.g., the DNA of SEQ ID NO:1), but more preferably, is anon-human homologue of a human CRF2-13 gene. For example, a mousehomologue of human CRF2-13 gene of SEQ ID NO:1 can be used to constructa homologous recombination vector suitable for altering an endogenousCRF2-13 gene in the mouse genome. In one embodiment, the vector isdesigned such that, upon homologous recombination, the endogenousCRF2-13 gene is functionally disrupted (i.e., no longer encodes afunctional protein; also referred to as a “knock out” vector).

[0243] Alternatively, the vector can be designed such that, uponhomologous recombination, the endogenous CRF2-13 gene is mutated orotherwise altered but still encodes functional protein (e.g., theupstream regulatory region can be altered to thereby alter theexpression of the endogenous CRF2-13 protein). In the homologousrecombination vector, the altered portion of the CRF2-13 gene is flankedat its 5′- and 3′-termini by additional nucleic acid of the CRF2-13 geneto allow for homologous recombination to occur between the exogenousCRF2-13 gene carried by the vector and an endogenous CRF2-13 gene in anembryonic stem cell. The additional flanking CRF2-13 nucleic acid is ofsufficient length for successful homologous recombination with theendogenous gene. Typically, several kilobases of flanking DNA (both atthe 5′- and 3′-termini) are included in the vector. See, e.g., Thomas,et al., 1987. Cell 51: 503 for a description of homologous recombinationvectors. The vector is ten introduced into an embryonic stem cell line(e.g., by electroporation) and cells in which the introduced CRF2-13gene has homologously-recombined with the endogenous CRF2-13 gene areselected. See, e.g., Li, et al., 1992. Cell 69: 915.

[0244] The selected cells are then injected into a blastocyst of ananimal (e.g., a mouse) to form aggregation chimeras. See, e.g., Bradley,1987. In: TERATOCARCINOMAS AND EMBRYONIC STEM CELLS: A PRACTICALAPPROACH, Robertson, ed. IRL, Oxford, pp. 113-152. A chimeric embryo canthen be implanted into a suitable pseudopregnant female foster animaland the embryo brought to term. Progeny harboring thehomologously-recombined DNA in their germ cells can be used to breedanimals in which all cells of the animal contain thehomologously-recombined DNA by germline transmission of the transgene.Methods for constructing homologous recombination vectors and homologousrecombinant animals are described further in Bradley, 1991. Curr. Opin.Biotechnol. 2: 823-829; PCT International Publication Nos.: WO 90/11354;WO 91/01140; WO 92/0968; and WO 93/04169.

[0245] In another embodiment, transgenic non-humans animals can beproduced that contain selected systems that allow for regulatedexpression of the transgene. One example of such a system is thecre/loxP recombinase system of bacteriophage P1. For a description ofthe cre/loxP recombinase system, See, e.g., Lakso, et al., 1992. Proc.Natl. Acad. Sci. USA 89: 6232-6236. Another example of a recombinasesystem is the FLP recombinase system of Saccharomyces cerevisiae. See,O'Gorman, et al., 1991. Science 251:1351-1355. If a cre/loxP recombinasesystem is used to regulate expression of the transgene, animalscontaining transgenes encoding both the Cre recombinase and a selectedprotein are required. Such animals can be provided through theconstruction of “double” transgenic animals, e.g., by mating twotransgenic animals, one containing a transgene encoding a selectedprotein and the other containing a transgene encoding a recombinase.

[0246] Clones of the non-human transgenic animals described herein canalso be produced according to the methods described in Wilmut, et al.,1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) fromthe transgenic animal can be isolated and induced to exit the growthcycle and enter G₀ phase. The quiescent cell can then be fused, e.g.,through the use of electrical pulses, to an enucleated oocyte from ananimal of the same species from which the quiescent cell is isolated.The reconstructed oocyte is then cultured such that it develops tomorula or blastocyte and then transferred to pseudopregnant femalefoster animal. The offspring borne of this female foster animal will bea clone of the animal from which the cell (e.g., the somatic cell) isisolated.

[0247] Pharmaceutical Compositions

[0248] The CRF2-13 nucleic acid molecules, CRF2-13 proteins, andanti-CRF2-13 antibodies (also referred to herein as “active compounds”)of the invention, and derivatives, fragments, analogs and homologsthereof, can be incorporated into pharmaceutical compositions suitablefor administration. Such compositions typically comprise the nucleicacid molecule, protein, or antibody and a pharmaceutically acceptablecarrier. As used herein, “pharmaceutically acceptable carrier” isintended to include any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration.Suitable carriers are described in the most recent edition ofRemington's Pharmaceutical Sciences, a standard reference text in thefield, which is incorporated herein by reference. Preferred examples ofsuch carriers or diluents include, but are not limited to, water,saline, finger's solutions, dextrose solution, and 5% human serumalbumin. Liposomes and non-aqueous vehicles such as fixed oils may alsobe used. The use of such media and agents for pharmaceutically activesubstances is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active compound, use thereof inthe compositions is contemplated. Supplementary active compounds canalso be incorporated into the compositions.

[0249] The antibodies disclosed herein can also be formulated asimmunoliposomes. Liposomes containing the antibody are prepared bymethods known in the art, such as described in Epstein et al., Proc.Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl. Acad.Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545.Liposomes with enhanced circulation time are disclosed in U.S. Pat. No.5,013,556.

[0250] Particularly useful liposomes can be generated by thereverse-phase evaporation method with a lipid composition comprisingphosphatidylcholine, cholesterol, and PEG-derivatizedphosphatidylethanolamine (PEG-PE). Liposomes are extruded throughfilters of defined pore size to yield liposomes with the desireddiameter. Fab′ fragments of the antibody of the present invention can beconjugated to the liposomes as described in Martin et al., J. Biol.Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. Achemotherapeutic agent (such as Doxorubicin) is optionally containedwithin the liposome. See Gabizon et al., J. National Cancer Inst.,81(19): 1484 (1989).

[0251] A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical),transmucosal, and rectal administration. Solutions or suspensions usedfor parenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid(EDTA); buffers such as acetates, citrates or phosphates, and agents forthe adjustment of tonicity such as sodium chloride or dextrose. The pHcan be adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

[0252] Pharmaceutical compositions suitable for injectable use includesterile aqueous solutions (where water soluble) or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

[0253] Sterile injectable solutions can be prepared by incorporating theactive compound (e.g., a CRF2-13 protein or anti-CRF2-13 antibody) inthe required amount in an appropriate solvent with one or a combinationof ingredients enumerated above, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating theactive compound into a sterile vehicle that contains a basic dispersionmedium and the required other ingredients from those enumerated above.In the case of sterile powders for the preparation of sterile injectablesolutions, methods of preparation are vacuum drying and freeze-dryingthat yields a powder of the active ingredient plus any additionaldesired ingredient from a previously sterile-filtered solution thereof.

[0254] Oral compositions generally include an inert diluent or an ediblecarrier. They can be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules. Oral compositions can also be preparedusing a fluid carrier for use as a mouthwash, wherein the compound inthe fluid carrier is applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

[0255] For administration by inhalation, the compounds are delivered inthe form of an aerosol spray from pressured container or dispenser whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

[0256] Systemic administration can also be by transmucosal ortransdermal means. For transmucosal or transdermal administration,penetrants appropriate to the barrier to be permeated are used in theformulation. Such penetrants are generally known in the art, andinclude, for example, for transmucosal administration, detergents, bilesalts, and fusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

[0257] The compounds can also be prepared in the form of suppositories(e.g., with conventional suppository bases such as cocoa butter andother glycerides) or retention enemas for rectal delivery.

[0258] In one embodiment, the active compounds are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

[0259] It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such an active compound for thetreatment of individuals.

[0260] The nucleic acid molecules of the invention can be inserted intovectors and used as gene therapy vectors. Gene therapy vectors can bedelivered to a subject by, for example, intravenous injection, localadministration (see, e.g., U.S. Pat. No. 5,328,470) or by stereotacticinjection (see, e.g., Chen, et al., 1994. Proc. Natl. Acad. Sci. USA 91:3054-3057). The pharmaceutical preparation of the gene therapy vectorcan include the gene therapy vector in an acceptable diluent, or cancomprise a slow release matrix in which the gene delivery vehicle isimbedded. Alternatively, where the complete gene delivery vector can beproduced intact from recombinant cells, e.g., retroviral vectors, thepharmaceutical preparation can include one or more cells that producethe gene delivery system.

[0261] Antibodies specifically binding a protein of the invention, aswell as other molecules identified by the screening assays disclosedherein, can be administered for the treatment of various disorders inthe form of pharmaceutical compositions. Principles and considerationsinvolved in preparing such compositions, as well as guidance in thechoice of components are provided, for example, in Remington: TheScience And Practice Of Pharmacy 19th ed. (Alfonso R. Gennaro, et al.,editors) Mack Pub. Co., Easton, Pa.: 1995; Drug Absorption Enhancement:Concepts, Possibilities, Limitations, And Trends, Harwood AcademicPublishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery(Advances In Parenteral Sciences, Vol. 4), 1991, M. Dekker, New York. Ifthe antigenic protein is intracellular and whole antibodies are used asinhibitors, internalizing antibodies are preferred. However, liposomescan also be used to deliver the antibody, or an antibody fragment, intocells. Where antibody fragments are used, the smallest inhibitoryfragment that specifically binds to the binding domain of the targetprotein is preferred. For example, based upon the variable-regionsequences of an antibody, peptide molecules can be designed that retainthe ability to bind the target protein sequence. Such peptides can besynthesized chemically and/or produced by recombinant DNA technology.See, e.g., Marasco et al., 1993 Proc. Natl. Acad. Sci. USA, 90:7889-7893. The formulation herein can also contain more than one activecompound as necessary for the particular indication being treated,preferably those with complementary activities that do not adverselyaffect each other. Alternatively, or in addition, the composition cancomprise an agent that enhances its function, such as, for example, acytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitoryagent. Such molecules are suitably present in combination in amountsthat are effective for the purpose intended. The active ingredients canalso be entrapped in microcapsules prepared, for example, bycoacervation techniques or by interfacial polymerization, for example,hydroxymethylcellulose or gelatin-microcapsules andpoly-(methylmethacrylate) microcapsules, respectively, in colloidal drugdelivery systems (for example, liposomes, albumin microspheres,microemulsions, nano-particles, and nanocapsules) or in macroemulsions.

[0262] The formulations to be used for in vivo administration must besterile. This is readily accomplished by filtration through sterilefiltration membranes.

[0263] Sustained-release preparations can be prepared. Suitable examplesof sustained-release preparations include semipermeable matrices ofsolid hydrophobic polymers containing the antibody, which matrices arein the form of shaped articles, e.g., films, or microcapsules. Examplesof sustained-release matrices include polyesters, hydrogels (forexample, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)),polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acidand y ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid.While polymers such as ethylene-vinyl acetate and lactic acid-glycolicacid enable release of molecules for over 100 days, certain hydrogelsrelease proteins for shorter time periods.

[0264] The pharmaceutical compositions can be included in a container,pack, or dispenser together with instructions for administration.

[0265] Screening and Detection Methods

[0266] The isolated nucleic acid molecules of the invention can be usedto express CRF2-13 protein (e.g., via a recombinant expression vector ina host cell in gene therapy applications), to detect CRF2-13 mRNA (e.g.,in a biological sample) or a genetic lesion in a CRF2-13 gene, and tomodulate CRF2-13 activity, as described further, below. In addition, theCRF2-13 proteins can be used to screen drugs or compounds that modulatethe CRF2-13 protein activity or expression as well as to treat disorderscharacterized by insufficient or excessive production of CRF2-13 proteinor production of CRF2-13 protein forms that have decreased or aberrantactivity compared to CRF2-13 wild-type protein. In addition, theanti-CRF2-13 antibodies of the invention can be used to detect andisolate CRF2-13 proteins and modulate CRF2-13 activity. For example,CRF2-13 activity includes T-cell or NK cell growth and differentiation,antibody production, and tumor growth.

[0267] The invention further pertains to novel agents identified by thescreening assays described herein and uses thereof for treatments asdescribed, supra.

[0268] Screening Assays

[0269] The invention provides a method (also referred to herein as a“screening assay”) for identifying modulators, i.e., candidate or testcompounds or agents (e.g., peptides, peptidomimetics, small molecules orother drugs) that bind to CRF2-13 proteins or have a stimulatory orinhibitory effect on, e.g., CRF2-13 protein expression or CRF2-13protein activity. The invention also includes compounds identified inthe screening assays described herein.

[0270] In one embodiment, the invention provides assays for screeningcandidate or test compounds which bind to or modulate the activity ofthe membrane-bound form of a CRF2-13 protein or polypeptide orbiologically-active portion thereof. The test compounds of the inventioncan be obtained using any of the numerous approaches in combinatoriallibrary methods known in the art, including: biological libraries;spatially addressable parallel solid phase or solution phase libraries;synthetic library methods requiring deconvolution; the “one-beadone-compound” library method; and synthetic library methods usingaffinity chromatography selection. The biological library approach islimited to peptide libraries, while the other four approaches areapplicable to peptide, non-peptide oligomer or small molecule librariesof compounds. See, e.g., Lam, 1997. Anticancer Drug Design 12: 145.

[0271] A “small molecule” as used herein, is meant to refer to acomposition that has a molecular weight of less than about 5 kD and mostpreferably less than about 4 kD. Small molecules can be, e.g., nucleicacids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids orother organic or inorganic molecules. Libraries of chemical and/orbiological mixtures, such as fungal, bacterial, or algal extracts, areknown in the art and can be screened with any of the assays of theinvention.

[0272] Examples of methods for the synthesis of molecular libraries canbe found in the art, for example in: DeWitt, et al., 1993. Proc. Natl.Acad. Sci. U.S.A. 90: 6909; Erb, et al., 1994. Proc. Natl. Acad. Sci.U.S.A. 91: 11422; Zuckermann, et al., 1994. J. Med. Chem. 37: 2678; Cho,et al., 1993. Science 261: 1303; Carrell, et al., 1994. Angew. Chem.Int. Ed. Engl. 33: 2059; Carell, et al., 1994. Angew. Chem. Int. Ed.Engl. 33: 2061; and Gallop, et al., 1994. J. Med. Chem. 37: 1233.

[0273] Libraries of compounds may be presented in solution (e.g.,Houghten, 1992. Biotechniques 13: 412-421), or on beads (Lam, 1991.Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556),bacteria (Ladner, U.S. Pat. No. 5,223,409), spores (Ladner, U.S. Pat.No. 5,233,409), plasmids (Cull, et al., 1992. Proc. Natl. Acad. Sci. USA89: 1865-1869) or on phage (Scott and Smith, 1990. Science 249: 386-390;Devlin, 1990. Science 249: 404-406; Cwirla, et al., 1990. Proc. Natl.Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991. J. Mol. Biol. 222:301-310; Ladner, U.S. Pat. No. 5,233,409.).

[0274] In one embodiment, an assay is a cell-based assay in which a cellwhich expresses a membrane-bound form of CRF2-13 protein, or abiologically-active portion thereof, on the cell surface is contactedwith a test compound and the ability of the test compound to bind to aCRF2-13 protein determined. The cell, for example, can be of mammalianorigin or a yeast cell. Determining the ability of the test compound tobind to the CRF2-13 protein can be accomplished, for example, bycoupling the test compound with a radioisotope or enzymatic label suchthat binding of the test compound to the CRF2-13 protein orbiologically-active portion thereof can be determined by detecting thelabeled compound in a complex. For example, test compounds can belabeled with ¹²⁵I, ³⁵S, ¹⁴C, or ³H, either directly or indirectly, andthe radioisotope detected by direct counting of radioemission or byscintillation counting. Alternatively, test compounds can beenzymatically-labeled with, for example, horseradish peroxidase,alkaline phosphatase, or luciferase, and the enzymatic label detected bydetermination of conversion of an appropriate substrate to product. Inone embodiment, the assay comprises contacting a cell which expresses amembrane-bound form of CRF2-13 protein, or a biologically-active portionthereof, on the cell surface with a known compound which binds CRF2-13to form an assay mixture, contacting the assay mixture with a testcompound, and determining the ability of the test compound to interactwith a CRF2-13 protein, wherein determining the ability of the testcompound to interact with a CRF2-13 protein comprises determining theability of the test compound to preferentially bind to CRF2-13 proteinor a biologically-active portion thereof as compared to the knowncompound.

[0275] In another embodiment, an assay is a cell-based assay comprisingcontacting a cell expressing a membrane-bound form of CRF2-13 protein,or a biologically-active portion thereof, on the cell surface with atest compound and determining the ability of the test compound tomodulate (e.g., stimulate or inhibit) the activity of the CRF2-13protein or biologically-active portion thereof. Determining the abilityof the test compound to modulate the activity of CRF2-13 or abiologically-active portion thereof can be accomplished, for example, bydetermining the ability of the CRF2-13 protein to bind to or interactwith a CRF2-13 target molecule. As used herein, a “target molecule” is amolecule with which a CRF2-13 protein binds or interacts in nature, forexample, a molecule on the surface of a cell which expresses a CRF2-13interacting protein, a molecule on the surface of a second cell, amolecule in the extracellular milieu, a molecule associated with theinternal surface of a cell membrane or a cytoplasmic molecule. A CRF2-13target molecule can be a non-CRF2-13 molecule or a CRF2-13 protein orpolypeptide of the invention In one embodiment, a CRF2-13 targetmolecule is a component of a signal transduction pathway thatfacilitates transduction of an extracellular signal (e.g. a signalgenerated by binding of a compound to a membrane-bound CRF2-13 molecule)through the cell membrane and into the cell. The target, for example,can be a second intercellular protein that has catalytic activity or aprotein that facilitates the association of downstream signalingmolecules with CRF2-13.

[0276] Determining the ability of the CRF2-13 protein to bind to orinteract with a CRF2-13 target molecule can be accomplished by one ofthe methods described above for determining direct binding. In oneembodiment, determining the ability of the CRF2-13 protein to bind to orinteract with a CRF2-13 target molecule can be accomplished bydetermining the activity of the target molecule. For example, theactivity of the target molecule can be determined by detecting inductionof a cellular second messenger of the target (i.e. intracellular Ca²⁺,diacylglycerol, IP₃, etc.), detecting catalytic/enzymatic activity ofthe target an appropriate substrate, detecting the induction of areporter gene (comprising a CRF2-13-responsive regulatory elementoperatively linked to a nucleic acid encoding a detectable marker, e.g.,luciferase), or detecting a cellular response, for example, cellsurvival, cellular differentiation, or cell proliferation.

[0277] In yet another embodiment, an assay of the invention is acell-free assay comprising contacting a CRF2-13 protein orbiologically-active portion thereof with a test compound and determiningthe ability of the test compound to bind to the CRF2-13 protein orbiologically-active portion thereof. Binding of the test compound to theCRF2-13 protein can be determined either directly or indirectly asdescribed above. In one such embodiment, the assay comprises contactingthe CRF2-13 protein or biologically-active portion thereof with a knowncompound which binds CRF2-13 to form an assay mixture, contacting theassay mixture with a test compound, and determining the ability of thetest compound to interact with a CRF2-13 protein, wherein determiningthe ability of the test compound to interact with a CRF2-13 proteincomprises determining the ability of the test compound to preferentiallybind to CRF2-13 or biologically-active portion thereof as compared tothe known compound.

[0278] In still another embodiment, an assay is a cell-free assaycomprising contacting CRF2-13 protein or biologically-active portionthereof with a test compound and determining the ability of the testcompound to modulate (e.g. stimulate or inhibit) the activity of theCRF2-13 protein or biologically-active portion thereof. Determining theability of the test compound to modulate the activity of CRF2-13 can beaccomplished, for example, by determining the ability of the CRF2-13protein to bind to a CRF2-13 target molecule by one of the methodsdescribed above for determining direct binding. In an alternativeembodiment, determining the ability of the test compound to modulate theactivity of CRF2-13 protein can be accomplished by determining theability of the CRF2-13 protein further modulate a CRF2-13 targetmolecule. For example, the catalytic/enzymatic activity of the targetmolecule on an appropriate substrate can be determined as describedabove.

[0279] In yet another embodiment, the cell-free assay comprisescontacting the CRF2-13 protein or biologically-active portion thereofwith a known compound which binds CRF2-13 protein to form an assaymixture, contacting the assay mixture with a test compound, anddetermining the ability of the test compound to interact with a CRF2-13protein, wherein determining the ability of the test compound tointeract with a CRF2-13 protein comprises determining the ability of theCRF2-13 protein to preferentially bind to or modulate the activity of aCRF2-13 target molecule.

[0280] The cell-free assays of the invention are amenable to use of boththe soluble form or the membrane-bound form of CRF2-13 protein. In thecase of cell-free assays comprising the membrane-bound form of CRF2-13protein, it may be desirable to utilize a solubilizing agent such thatthe membrane-bound form of CRF2-13 protein is maintained in solution.Examples of such solubilizing agents include non-ionic detergents suchas n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside,octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton® X-100,Triton® X-114, Thesit®, Isotridecypoly(ethylene glycol ether)_(n),N-dodecyl—N,N-dimethyl-3-ammonio-1-propane sulfonate,3-(3-cholamidopropyl) dimethylamminiol-1-propane sulfonate (CHAPS), or3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1-propane sulfonate(CHAPSO).

[0281] In more than one embodiment of the above assay methods of theinvention, it may be desirable to immobilize either CRF2-13 protein orits target molecule to facilitate separation of complexed fromuncomplexed forms of one or both of the proteins, as well as toaccommodate automation of the assay. Binding of a test compound toCRF2-13 protein, or interaction of CRF2-13 protein with a targetmolecule in the presence and absence of a candidate compound, can beaccomplished in any vessel suitable for containing the reactants.Examples of such vessels include microtiter plates, test tubes, andmicro-centrifuge tubes. In one embodiment, a fusion protein can beprovided that adds a domain that allows one or both of the proteins tobe bound to a matrix. For example, GST-CRF2-13 fusion proteins orGST-target fusion proteins can be adsorbed onto glutathione sepharosebeads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatizedmicrotiter plates, that are then combined with the test compound or thetest compound and either the non-adsorbed target protein or CRF2-13protein, and the mixture is incubated under conditions conducive tocomplex formation (e.g., at physiological conditions for salt and pH).Following incubation, the beads or microtiter plate wells are washed toremove any unbound components, the matrix immobilized in the case ofbeads, complex determined either directly or indirectly, for example, asdescribed, supra. Alternatively, the complexes can be dissociated fromthe matrix, and the level of CRF2-13 protein binding or activitydetermined using standard techniques.

[0282] Other techniques for immobilizing proteins on matrices can alsobe used in the screening assays of the invention. For example, eitherthe CRF2-13 protein or its target molecule can be immobilized utilizingconjugation of biotin and streptavidin. Biotinylated CRF2-13 protein ortarget molecules can be prepared from biotin-NHS(N-hydroxy-succinimide)using techniques well-known within the art (e.g., biotinylation kit,Pierce Chemicals, Rockford, Ill.), and immobilized in the wells ofstreptavidin-coated 96 well plates (Pierce Chemical). Alternatively,antibodies reactive with CRF2-13 protein or target molecules, but whichdo not interfere with binding of the CRF2-13 protein to its targetmolecule, can be derivatized to the wells of the plate, and unboundtarget or CRF2-13 protein trapped in the wells by antibody conjugation.Methods for detecting such complexes, in addition to those describedabove for the GST-immobilized complexes, include immunodetection ofcomplexes using antibodies reactive with the CRF2-13 protein or targetmolecule, as well as enzyme-linked assays that rely on detecting anenzymatic activity associated with the CRF2-13 protein or targetmolecule.

[0283] In another embodiment, modulators of CRF2-13 protein expressionare identified in a method wherein a cell is contacted with a candidatecompound and the expression of CRF2-13 mRNA or protein in the cell isdetermined. The level of expression of CRF2-13 mRNA or protein in thepresence of the candidate compound is compared to the level ofexpression of CRF2-13 mRNA or protein in the absence of the candidatecompound. The candidate compound can then be identified as a modulatorof CRF2-13 mRNA or protein expression based upon this comparison. Forexample, when expression of CRF2-13 mRNA or protein is greater (i.e.,statistically significantly greater) in the presence of the candidatecompound than in its absence, the candidate compound is identified as astimulator of CRF2-13 mRNA or protein expression. Alternatively, whenexpression of CRF2-13 mRNA or protein is less (statisticallysignificantly less) in the presence of the candidate compound than inits absence, the candidate compound is identified as an inhibitor ofCRF2-13 mRNA or protein expression. The level of CRF2-13 mRNA or proteinexpression in the cells can be determined by methods described hereinfor detecting CRF2-13 mRNA or protein.

[0284] In yet another aspect of the invention, the CRF2-13 proteins canbe used as “bait proteins” in a two-hybrid assay or three hybrid assay(see, e.g., U.S. Pat. No. 5,283,317; Zervos, et al., 1993. Cell 72:223-232; Madura, et al., 1993. J. Biol. Chem. 268: 12046-12054; Bartel,et al., 1993. Biotechniques 14: 920-924; Iwabuchi, et al., 1993.Oncogene 8: 1693-1696; and Brent WO 94/10300), to identify otherproteins that bind to or interact with CRF2-13 (“CRF2-13-bindingproteins” or “CRF2-13-bp”) and modulate CRF2-13 activity. SuchCRF2-13-binding proteins are also likely to be involved in thepropagation of signals by the CRF2-13 proteins as, for example, upstreamor downstream elements of the CRF2-13 pathway.

[0285] The two-hybrid system is based on the modular nature of mosttranscription factors, which consist of separable DNA-binding andactivation domains. Briefly, the assay utilizes two different DNAconstructs. In one construct, the gene that codes for CRF2-13 is fusedto a gene encoding the DNA binding domain of a known transcriptionfactor (e.g., GAL-4). In the other construct, a DNA sequence, from alibrary of DNA sequences, that encodes an unidentified protein (“prey”or “sample”) is fused to a gene that codes for the activation domain ofthe known transcription factor. If the “bait” and the “prey” proteinsare able to interact, in vivo, forming a CRF2-13-dependenht complex, theDNA-binding and activation domains of the transcription factor arebrought into close proximity. This proximity allows transcription of areporter gene (e.g., LacZ) that is operably linked to a transcriptionalregulatory site responsive to the transcription factor. Expression ofthe reporter gene can be detected and cell colonies containing thefunctional transcription factor can be isolated and used to obtain thecloned gene that encodes the protein which interacts with CRF2-13.

[0286] The invention further pertains to novel agents identified by theaforementioned screening assays and uses thereof for treatments asdescribed herein.

[0287] The invention will be further illustrated in the followingnon-limiting examples.

EXAMPLE 1 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0288] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:4. Thevariant amino acid sequence is shown in bold-font. A valine at position30 in the polypeptide sequence shown in SEQ ID NO:2 is replaced with analanine in SEQ ID NO:4. (SEQ ID NO:4)MAGPERWGPLLLCLLQAAPGRPRLAPPQNATLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWOTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 2 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0289] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:5. Thevariant amino acid sequence is shown in bold-font. A leucine at position39 in the polypeptide sequence shown in SEQ ID NO:2 is replaced with anisoleucine in SEQ ID NO:5. (SEQ ID NO:5)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYITWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEOAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 3 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0290] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:6. Thevariant amino acid sequence is shown in bold-font. An asparagine atposition 49 in the polypeptide sequence shown in SEQ ID NO:2 is replacedwith a threonine in SEQ ID NO:6. (SEQ ID NO:5)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGTPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 4 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0291] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:7. Thevariant amino acid sequence is shown in bold-font. An arginine atposition 65 in the polypeptide sequence shown in SEQ ID NO:2 is replacedwith a lysine in SEQ ID NO:7. (SEQ ID NO:7)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTKRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 5 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0292] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:8. Thevariant amino acid sequence is shown in bold-font. A lysine at position78 in the polypeptide sequence shown in SEQ ID NO:2 is replaced with anarginine in SEQ ID NO:8. (SEQ ID NO:8)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTR]ELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDL]KYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPS]LLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPA]TQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSW]ASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVS] LQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 6 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0293] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:9. Thevariant amino acid sequence is shown in bold-font. A Q {glutamine?}atposition 90 in the polypeptide sequence shown in SEQ ID NO:2 is replacedwith an asparagine in SEQ ID NO:9. (SEQ ID NO:9)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKNDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 7 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0294] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:10. Thevariant amino acid sequence is shown in bold-font. A arginine atposition 99 in the polypeptide sequence shown in SEQ ID NO:2 is replacedwith an lysine in SEQ ID NO:10. (SEQ ID NO:10)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGKVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLOQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 8 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0295] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:11. Thevariant amino acid sequence is shown in bold-font. A valine at position112 in the polypeptide sequence shown in SEQ ID NO:2 is replaced with anleucine in SEQ ID NO:.11. (SEQ ID NO:11)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWLESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 9 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0296] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:12. Thevariant amino acid sequence is shown in bold-font. A tyrosine atposition 119 in the polypeptide sequence shown in SEQ ID NO:2 isreplaced with a phenylalanine in SEQ ID NO:12. (SEQ ID NO:12)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWLESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

Example 10 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0297] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:13. Thevariant amino acid sequence is shown in bold-font. A valine at position129 in the polypeptide sequence shown in SEQ ID NO:2 is replaced with anisoleucine in SEQ ID NO:13. (SEQ ID NO:13)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPILVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSOHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSORPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 11 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0298] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:14. Thevariant amino acid sequence is shown in bold-font. A threonine atposition 144 in the polypeptide sequence shown in SEQ ID NO:2 isreplaced with an asparagine in SEQ ID NO:14. (SEQ ID NO:14)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANANYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 12 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0299] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:15. Thevariant amino acid sequence is shown in bold-font. A leucine at position154 in the polypeptide sequence shown in SEQ ID NO:2 is replaced with analanine in SEQ ID NO:15. (SEQ ID NO:15)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPADLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 13 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0300] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:16. Thevariant amino acid sequence is shown in bold-font. A lysine at position170 in the polypeptide sequence shown in SEQ ID NO:2 is replaced with anarginine in SEQ ID NO:16. (SEQ ID NO:16)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNRTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 14 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0301] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:17. Thevariant amino acid sequence is shown in bold-font. A valine at position175 in the polypeptide sequence shown in SEQ ID NO:2 is replaced with aleucine in SEQ ID NO:17. (SEQ ID NO:17)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPLTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 15 A sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0302] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:18. Thevariant amino acid sequence is shown in bold-font. An alanine atposition 189 in the polypeptide sequence shown in SEQ ID NO:2 isreplaced with a valine in SEQ ID NO:18. (SEQ ID NO:18)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPVASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPOHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWOAESTQRTEDRGRTLGHYMAR

Example 16 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0303] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:19 Thevariant amino acid sequence is shown in bold-font. An arginine atposition 199 in the polypeptide sequence shown in SEQ ID NO:2 isreplaced with a lysine in SEQ ID NO:.19MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTK(SEQ ID NO:19)ELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKWSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

EXAMPLE 17 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0304] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:20. Thevariant amino acid sequence is shown in bold-font. A phenylalanine atposition 212 in the polypeptide sequence shown in SEQ ID NO:2 isreplaced with an a tryptophan in SEQ ID NO:20. (SEQ ID NO:20)MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKWSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGHQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR

Example 18 A Sequence Variant of the Disclosed CRF2-13 Polypeptide AminoAcid Sequence (SEQ ID NO:2)

[0305] A polypeptide sequence differing by one amino acid sequence fromthe amino acid sequence of SEQ ID NO:2 is shown in SEQ ID NO:21. Thevariant amino acid sequence is shown in bold-font. An arginine atposition 230 in the polypeptide sequence shown in SEQ ID NO:2 isreplaced with a lysine in SEQ ID NO21:. (SEQ ID NO:21)MAGPERWGPLLLCLLQAAPORPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQSSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYLFEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQPVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLLVIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTRGVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHSEAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDGEQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSPEEEEEARESEIEDSDACSWGAESTQRTEDRGRTLGHYMAK

EXAMPLE 19 Identification of a CRF2-13 Sequence in a Human PlacentalcDNA Library

[0306] A 310 nucleotide fragment corresponding to nucleotides XX to XX[41-352 of SEQ ID No.1] in Table 1 was identified in a human placentalcDNA library (BD Biosciences Clontech, Palo Alto, Calif., USA) by PCRusing an Advantage II PCR kit (BD Biosciences Clontech, Palo Alto,Calif., USA) and primers specific for the 5′ region of the humanCRF2-13. The primers included Ax5-1 (GCTGCAGGCCGCTCCAGGGAGGCCCCG; SEQID:23) and Ax3-1 (CCAGGTATTCGGACTCCACCCAGGGGGAC; SEQ ID NO:24). Theprimers were used for thirty eight thermal cycles of PCR. The CRF2-13nucleic acid product was gel purified and sequenced. The sequencecorresponds to the corresponding sequences in the CRF2-13 sequencedisclosed in Table 1.

[0307] Based on these findings a Rapid-Screen™ Arrayed cDNA LibraryPanel of Human Placenta Sub-Plate 2H (Origene Technologies, Inc.,Rockville, Md., USA) was selected for screening and isolation of theCFR2-13 clone coding for the mature protein. [11-1563 of SEQ ID No.1].The existence of the first 10 bases of SEQ ID No.1 was verified by PCR.The library quality was improved by first isolating double-strandedcDNAs of different size-fractions and then ligating them separately intothe vector. The cDNA library is arrayed in a 96-well plates.

[0308] Since the cDNAs of the Human Placenta Sub-Plate 2H humanplacental library were directionally-cloned into the CMV expressionvector pCMV6-XL4, a vector-derived 5′ PCR primer was used in conjunctionwith a gene-specific 3′ reverse primer to identify the CRF2-13 clone. Inthis study, the cDNA library was screened by a PCR-based procedure usingthe Advantage II PCR kit (BD Biosciences Clontech, Palo Alto, Calif.,USA) and Ax5-1 (SEQ ID:25 and Ax3-2 (TTGGTTCCCGCACACTCTTCCACTTCG; SEQ IDNO:26) as PCR primers. PCR analysis was carried out in a 96-well arrayedat 50 clones per well. The PCR positive well (E2) was identified and theE. coli cells from that well were subsequently diluted, plated out andanalyzed to yield the clone full-length CRF2-13 clone. The identity ofthe CRF2-13 clone was then verified by sequence analysis.

Other Embodiments

[0309] While the invention has been described in conjunction with thedetailed description thereof, the foregoing description is intended toillustrate and not limit the scope of the invention, which is defined bythe scope of the appended claims. Other aspects, advantages, andmodifications are within the scope of the following claims.

1 33 1 1563 DNA Homo sapiens 1 atggcggggc ccgagcgctg gggccccctgctcctgtgcc tgctgcaggc cgctccaggg 60 aggccccgtc tggcccctcc ccagaatgtgacgctgctct cccagaactt cagcgtgtac 120 ctgacatggc tcccagggct tggcaacccccaggatgtga cctattttgt ggcctatcag 180 agctctccca cccgtagacg gtggcgcgaagtggaagagt gtgcgggaac caaggagctg 240 ctatgttcta tgatgtgcct gaagaaacaggacctgtaca acaagttcaa gggacgcgtg 300 cggacggttt ctcccagctc caagtccccctgggtggagt ccgaatacct ggattacctt 360 tttgaagtgg agccggcccc acctgtcctggtgctcaccc agacggagga gatcctgagt 420 gccaatgcca cgtaccagct gcccccctgcatgcccccac tggatctgaa gtatgaggtg 480 gcattctgga aggagggggc cggaaacaagaccctatttc cagtcactcc ccatggccag 540 ccagtccaga tcactctcca gccagctgccagcgaacacc actgcctcag tgccagaacc 600 atctacacgt tcagtgtccc gaaatacagcaagttctcta agcccacctg cttcttgctg 660 gaggtcccag aagccaactg ggctttcctggtgctgccat cgcttctgat actgctgtta 720 gtaattgccg cagggggtgt gatctggaagaccctcatgg ggaacccctg gtttcagcgg 780 gcaaagatgc cacgggccct ggacttttctggacacacac accctgtggc aacctttcag 840 cccagcagac cagagtccgt gaatgacttgttcctctgtc cccaaaagga actgaccaga 900 ggggtcaggc cgacgcctcg agtcagggccccagccaccc aacagacaag atggaagaag 960 gaccttgcag aggacgaaga ggaggaggatgaggaggaca cagaagatgg cgtcagcttc 1020 cagccctaca ttgaaccacc ttctttcctggggcaagagc accaggctcc agggcactcg 1080 gaggctggtg gggtggactc agggaggcccagggctcctc tggtcccaag cgaaggctcc 1140 tctgcttggg attcttcaga cagaagctgggccagcactg tggactcctc ctgggacagg 1200 gctgggtcct ctggctattt ggctgagaaggggccaggcc aagggccggg tggggatggg 1260 caccaagaat ctctcccacc acctgaattctccaaggact cgggtttcct ggaagagctc 1320 ccagaagata acctctcctc ctgggccacctggggcacct taccaccgga gccgaatctg 1380 gtccctgggg gacccccagt ttctcttcagacactgacct tctgctggga aagcagccct 1440 gaggaggaag aggaggcgag ggaatcagaaattgaggaca gcgatgcggg cagctggggg 1500 gctgagagca cccagaggac cgaggacaggggccggacat tggggcatta catggccagg 1560 tga 1563 2 520 PRT Homo sapiens 2Met Ala Gly Pro Glu Arg Trp Gly Pro Leu Leu Leu Cys Leu Leu Gln 1 5 1015 Ala Ala Pro Gly Arg Pro Arg Leu Ala Pro Pro Gln Asn Val Thr Leu 20 2530 Leu Ser Gln Asn Phe Ser Val Tyr Leu Thr Trp Leu Pro Gly Leu Gly 35 4045 Asn Pro Gln Asp Val Thr Tyr Phe Val Ala Tyr Gln Ser Ser Pro Thr 50 5560 Arg Arg Arg Trp Arg Glu Val Glu Glu Cys Ala Gly Thr Lys Glu Leu 65 7075 80 Leu Cys Ser Met Met Cys Leu Lys Lys Gln Asp Leu Tyr Asn Lys Phe 8590 95 Lys Gly Arg Val Arg Thr Val Ser Pro Ser Ser Lys Ser Pro Trp Val100 105 110 Glu Ser Glu Tyr Leu Asp Tyr Leu Phe Glu Val Glu Pro Ala ProPro 115 120 125 Val Leu Val Leu Thr Gln Thr Glu Glu Ile Leu Ser Ala AsnAla Thr 130 135 140 Tyr Gln Leu Pro Pro Cys Met Pro Pro Leu Asp Leu LysTyr Glu Val 145 150 155 160 Ala Phe Trp Lys Glu Gly Ala Gly Asn Lys ThrLeu Phe Pro Val Thr 165 170 175 Pro His Gly Gln Pro Val Gln Ile Thr LeuGln Pro Ala Ala Ser Glu 180 185 190 His His Cys Leu Ser Ala Arg Thr IleTyr Thr Phe Ser Val Pro Lys 195 200 205 Tyr Ser Lys Phe Ser Lys Pro ThrCys Phe Leu Leu Glu Val Pro Glu 210 215 220 Ala Asn Trp Ala Phe Leu ValLeu Pro Ser Leu Leu Ile Leu Leu Leu 225 230 235 240 Val Ile Ala Ala GlyGly Val Ile Trp Lys Thr Leu Met Gly Asn Pro 245 250 255 Trp Phe Gln ArgAla Lys Met Pro Arg Ala Leu Asp Phe Ser Gly His 260 265 270 Thr His ProVal Ala Thr Phe Gln Pro Ser Arg Pro Glu Ser Val Asn 275 280 285 Asp LeuPhe Leu Cys Pro Gln Lys Glu Leu Thr Arg Gly Val Arg Pro 290 295 300 ThrPro Arg Val Arg Ala Pro Ala Thr Gln Gln Thr Arg Trp Lys Lys 305 310 315320 Asp Leu Ala Glu Asp Glu Glu Glu Glu Asp Glu Glu Asp Thr Glu Asp 325330 335 Gly Val Ser Phe Gln Pro Tyr Ile Glu Pro Pro Ser Phe Leu Gly Gln340 345 350 Glu His Gln Ala Pro Gly His Ser Glu Ala Gly Gly Val Asp SerGly 355 360 365 Arg Pro Arg Ala Pro Leu Val Pro Ser Glu Gly Ser Ser AlaTrp Asp 370 375 380 Ser Ser Asp Arg Ser Trp Ala Ser Thr Val Asp Ser SerTrp Asp Arg 385 390 395 400 Ala Gly Ser Ser Gly Tyr Leu Ala Glu Lys GlyPro Gly Gln Gly Pro 405 410 415 Gly Gly Asp Gly His Gln Glu Ser Leu ProPro Pro Glu Phe Ser Lys 420 425 430 Asp Ser Gly Phe Leu Glu Glu Leu ProGlu Asp Asn Leu Ser Ser Trp 435 440 445 Ala Thr Trp Gly Thr Leu Pro ProGlu Pro Asn Leu Val Pro Gly Gly 450 455 460 Pro Pro Val Ser Leu Gln ThrLeu Thr Phe Cys Trp Glu Ser Ser Pro 465 470 475 480 Glu Glu Glu Glu GluAla Arg Glu Ser Glu Ile Glu Asp Ser Asp Ala 485 490 495 Gly Ser Trp GlyAla Glu Ser Thr Gln Arg Thr Glu Asp Arg Gly Arg 500 505 510 Thr Leu GlyHis Tyr Met Ala Arg 515 520 3 34450 DNA Homo sapiens misc_feature(10013)..(10013) Wherein “N” is A, or T, or C, or G. 3 gaaagagagagaaaaaagaa ggaaggaagg aaggaaggaa ggaaggaagg aaggaaagaa 60 agaaagaaagaaagaaagaa agaaagaaag aaagaaagaa agagagagaa aggaaggaag 120 gaaggagaaaagaaagtcaa cagtcaacat ttcagagatc ccaagatacc aacactgacc 180 gtgcctgctgctcttccatc ctcctccacc ctgcgccttt gaggtggaat tgcgtcctct 240 gtgagcagggctttgttaag agatcctaat taaggccagg cacagtggct catgcctgta 300 atcccagcactttgggaggc tgaggtcacc tgaggtcagg agttcaagac cagcctgccc 360 aacatggtgaaaccccatct ctacaaaaat tagctgagca tgatggcagg tgcctgtaat 420 cccaactacttgggaggctg aagtgagaaa atagcttgaa cccaggaggc ggggttgcag 480 tgagccaagatcacactatt gcattccagc ctgggcgaca gagcttttgt ctaaaaaaaa 540 aaaaagaaaaaaaatcctga ttaagcagaa gccttgatgc tagtcccaga agcatcctga 600 aatttccaaaagaaatttcc cccgcggtta aactcagagc aacttttgga cccaccaagc 660 tctgtgaaaatcattttctc ttccaaaaac tgatgggacc aaagctgatc ccagtttcaa 720 ataattatcaaaaaattgga aacgaaatat gatcagaaaa gaagaaagtt gaaaaagaaa 780 atccttatcacccaaagaca acaaccatta atattttggt aattattatt acaaatatct 840 ttctatgcatacagacagac tcacacacac acacacacac acacacacac actttttttt 900 ttttttttgaaactgagttt cactctgtcg cccaggctgg agtgcagtgg cgcgatctcg 960 gctcactgcaacctccgcct cctgggttca agcgattctc ctgcctcagc ctccctgata 1020 gctgggattacaggtgaatg ccaccacgcc cggctgattt tctgtatttt tagtagagac 1080 ggggtttcaccatgttggcc aggcttgtct ccaactcctg acctcaggcg atccacccgc 1140 ctcaccctcccaaagtgctg ggattacagg cgtgagccac cgcgcccggc tacacacaca 1200 cttttttaatgggcctatgt tttagcactc gcttttctgt ttctcagtgt gttgcaaaca 1260 cctcggtgtcgatacacacc attcggcaac gtcctcctaa agggccgcat aatattgcgc 1320 gtcgtggcgtgtgccttact gggaagctac tgctgtccag gtgaacacca cagccttcgg 1380 ggtcagaaagacagctttcc ccagaacaag cacctgaagc tctggggcct gccgctcccc 1440 gggtagagaagtacgtggag aagggcagca cggatccgcc gggatccccg ggggcattaa 1500 agggaatcgcgtgtgtaagg cgcggagctc agcatccggc tcagaaacgc gctcggatcc 1560 cgccaatggcattgaggccg cgtagccaaa ccggccttga actctcccta atcctgccaa 1620 aatggcccgtcctggagcac tggactggcc gtgggttatt gatcatcagc cggtttcttc 1680 ccctcccctgcccttccccc gtgcacggat ttactgattt ttttttccgg gaattgagta 1740 aaacaaaactaagtgcagat gaagcagagg tacgggcgag tttcgagcgc ggggaccggc 1800 gcgctcccccccccctcccc ccgcggcggg gctgtcccca gggaccttct cagtgaatcc 1860 taggcggcagggacgggccc gcggctctgc gggccattgg ctgccgactg cgtcacctgc 1920 ccgcggtgggctaggagacg ggaggcggga ggcgggaggc ggggacctgg gtccgggcgg 1980 ggacgccgcggcaggaaggc catggcgggg cccgagcgct ggggccccct gctcctgtgc 2040 ctgctgcaggccgctccagg taagggcgcg gggccgcggg agggaggggg aagagggctc 2100 cccgggccgggccgcgccta ccctcggacc cagagctcct gggacaggca cggggtccgc 2160 agccacccgagccgggtgcg aatcggccct gcctacgcgc ccccagtttg cttcttccca 2220 ggactgaacagaaccgggtc tttgatattc ctctcccgca ggaaacgaat ccagtttcct 2280 aatgcttccagcttcaggag aactggagaa aaaagacagc ggcagtttga tactgcatat 2340 tttttaataaagtgcttttt aatgtttcct aaagaaagca ctgatccctg cgtgaaaacc 2400 acacttgaccctaaagtgtg gacagcaggg aaagtgggac cgattgatgt cccttcccgt 2460 tcctgccaggcctctggtgg gacggagctc tggtcgcctg tgccctgctt tctaacaaga 2520 cggctttcttttggtggtgg ttgttgtttt gttgttgttt tgttgttgtt gttgttgttg 2580 ttgttttcccacctctactg atgagtaagg tgtcaggtac aaaattcctc gccgtaggac 2640 ccaaccaccaaacctcaccg cccacgactc caaccgaagc agggaagaga aggtccagaa 2700 atcgcccccaggatattttc ctagtcttgg actcacagtt taaagagctg taaaggtccc 2760 tgggcataatccaatcatca taaaagccta tatttattca gcaacttctt tgtgccaggc 2820 accgcattattctggaagcc tcacgaccca gccatcctag gaggtagata ttatttttac 2880 ttttccgatgggaaaactga ggctcagagc aattcaggga attcctcaag aaggacggca 2940 gaggtgaggcacacagaaga gagaagaggg gctaaagcaa gcctggctag cttttgcctc 3000 cagggtaggcacgtgggaca ggctgtccat ccactgggtc actaggccag ccagggatgc 3060 tccagcccccagtgcccaca gcagcgttct ctgtggctga tgagggaccg tgtacctgtg 3120 tgtggagggagggtggggtc ttctgttccc ctttcactgt caagcccaga ccttcttgta 3180 ctttcacctgataagtattt aatatacaca acactaacta tggtgtgatg atttaggagt 3240 aagtacagccagatctaagt tcaaatactg gctcccacac aaactgactg tgtagcctca 3300 ggcaagttagttagcatctg tctctgagcc tagcgccctt tccatggaag cagaatgaat 3360 gacacctaccccatagggtg gtctgtccca agggtgattg aggttttaca tgtaaagagc 3420 caaactagtgcctggcatcc tttgaaggct tcatagagga aagttgctct agctgctgtt 3480 tttctcatgtgacctagctc gaatctgggg actgtcctgc ccataggata ccttacaagt 3540 ggcttgcagacagcctggtc tcctgctggt cacccgttag gaagtccaga agctgggagt 3600 agtaatagcactagcctcgt ggtgatacag tcccagctag aggacacagg atgaggtgga 3660 agcaggcacccacttttggg tctaaaaggt gatgggtagg cagccgaggc tggggacagc 3720 catccacagaactggaccct ccctccctga tgccattttg caacccgtat ggatttccat 3780 catggcacatgggacacttc aggaccctga attctccatg ggaccatgag ctcctatagg 3840 gcaggaatgaagttgtgttc ttctttgaaa cccctggcac accgtggtca acagatcttg 3900 tttgactcgtagtggtcaat agatggaata gttggaatca taaagctcaa tagaccccat 3960 gagaacctagaagacaaagt acagtcaaga gctcggactt tggagttggc taggcctgga 4020 ctgaatctgattctacaact taatagctga gagggccttg gttttcccat ctgtaaagat 4080 tataattattataatgaata cctacctcct agggatgtaa tgaggattaa aagagaaagt 4140 gcaggtaaactgtttaacac agaacctggc tcatagaaca caatacacat tagctgctat 4200 tattattattattattttat ttatttattt tgagacagag tctcactctg tcacccaggc 4260 tggagtgcagtggcgcaatc tcggctcact gcaacctcca cctatcgggt tcaagcaatt 4320 ctcgtgtctcagcctcccaa gtagctgaga tgacaggcgt gtgccaccat gcccaactaa 4380 tttttgtatttttagaagag acgtggtttc accatgttgg ccaggctggt ctcaaactcc 4440 tgacctcaggtgatttgcct acctctgcct cccaaaatgc tgggatcaca ggggtgagtt 4500 accatgcccggccttagctg ctattattat catcatcgtt atcatcatca tcatcacctc 4560 gtagatatgtcaaggaagat tccctggagg aagtgacatt tgaatcaagt atttcaaaga 4620 ctagatggtgaataccaggc agtcaaagac acctgggttt aaaaacatcc agaagaatgc 4680 agtggcttggcaacatcgag caggaagatt gcctgatgag cctgtagggt agctgttggg 4740 gagagagcagcaagacggcc tggccaggcc aggccaggcc acgtcaggca gggcctcaca 4800 aacctcaataacaaatgtgg actttattct gaggccaagg aaagggcatg aaactgggga 4860 gtggtgtaatcagatgcgta tttcagaaga tgaagattaa cagtgagaag gaaaatgtgc 4920 cacagaggggaatagaggtc agttaaaggg agtcagggaa agtgtcctcg agacagtgac 4980 atcaaaggaatgtgaaaaca gcaaaggagt gagccaggtg gatatccagg ggcagaactg 5040 ttaaggcagagggaacagca tgagggaaca gcgtgtgcaa aggcctggag ttgggagtgt 5100 ggctggggtgctccaggaag ggcaaaaagt cctgtgtgga tggagatatg ggagcaaggg 5160 aggagtggtgggtcagattg ggtagggcct tggtggtgat tgtaaagact ttggagttta 5220 gaccaggcacagtggctcag gcctgtaatc ccagcacttt gagaggccaa ggtgggcgga 5280 tcacctgaggtcaggagttc gagaccagcc tgtaatccca gctactctgg aggctgaggc 5340 aggagaatcgcttgaacccg gaaggtggag gttgcagtga gctgagattg tgccactgta 5400 ctccagcctgggtggcagca taagactctg cctcaaaata aaataaaaat aataaagact 5460 tttgagtttccctggagtga gaggaaagcc ttagagggct ttagcagaag atgaacatga 5520 tctgattttcatttttaatc cttccctgct aatgtggaga atggactgaa ggcaaggtgt 5580 tttgtatatttgtctgtttc gtagagacag ggtcttgctc tgttggccag actgaagtgc 5640 agtggcacaatcacggcagc cttgaactcc tgggctcagg cgaaactccc acctcagcct 5700 ccttactctcaccattgtgc cctgctaatt ttttaaaaaa tttattttgt agagatgtgg 5760 tctcactatgttgcctaggc aagtcttaaa ttcctggtct caaatgattc tcctgcctcg 5820 atgtcccaaagtgctgggat tacaggtgtc agctgccatg cccgacctgt attttttttt 5880 ttaatggggaaaaagccttt taatagtatg aggtgttttc tggtgtttct accataaagc 5940 tcttctgtaaatcaaaatga gaatgtaatt attgatagag caatgacctt agactacagt 6000 gcagacttttcatcttacat ttgggctcat gaattttagt ataactgatt atgacagtgt 6060 tttttacatagttatgatct agagcagaac tgaaaacaaa ataacacata ctctacatca 6120 atatattcgttcagtaatat ctgggcttgg atgaacctgc agaagtaggt aaagctgtca 6180 gatattttcttaaaccaaca gaaaagaaat gtatatgaca gatgttgtgt ttacttactt 6240 atttatttatttatttattt atttgagatg gagtctcact gtgtcaccag gctggagtac 6300 agtggtgtgatctctgctca ctgcaacctc cacctcccgg attcaagcga ttctcctgcc 6360 tcagcctcctgagtagctgg gattacaggc gtgcaccacc acgcctggct aatttttgtg 6420 tttttagtagagacagggtt tcaccatgtt ggtcaggctg gtctcgaact cctgacctcg 6480 ggatctgcccacatcagcct cccaaagtac tgggattaca ggcatgaacc accacgccca 6540 gcctgtatttatttttttac cactatggag tccaatatga aattctcaca actatgcata 6600 tacattattaacatgtaagc acacctaggt ataaatatgc acatagtcca ttaattacat 6660 caggggaattaaaaacatac tttcaagtta aaatgaattt tcaggaaaaa aactgcattc 6720 acaaatctgaaatgtgaata caaaaatgaa attgtgaaat aaataatgaa tataggtgtc 6780 acctaaacttccatagtaac atgcctccaa atgtggattt agtgatcatc caccttggga 6840 caagggcttttgagagcctc cagctaaatt agggttccag tagcagagtg gctggcaagc 6900 ctgccctaatgaataatgcc agcgagctgg gcgtgggtac ttacagtgtg cccttcatgg 6960 aatacttttttttttttttt tggaatggag tctcgccctg ttgcccaggc tggaatgcag 7020 tggcacaatctcagctcact gcaacctcgt cctcctgggt tcaagcaatt ctcgtgcctc 7080 agcctcccaggtagctgaga ctacagccct gtgccatcat gttctgctaa tttttgcatt 7140 tttagtagagacgaggtttc accaagttgg ccaagactgg tcttgaattc ctgacctcag 7200 gtgatctgcccaccttgacc tcccaaagtg ctgggattac aggcttgagc cactgcgccc 7260 ggcccatgaaatacttctta cctggcggac agcctaatag cctagctgtc taacccatgg 7320 ctgggggtccttcacacttg tttatactgg cagacgtccc tgtgactctt gtctgatcca 7380 tgtccaagtttatgcctgtc tgaccattgc tctggcgctg ggagccagac tgtgttccca 7440 gcaacccagggaaaaccagg cctgggctgg gcctgggttc ctgagatgga aggtgcaaat 7500 tcagtacaccacctcaatgc aaaacaagtt caaaggctta ttacttacag atcctgagca 7560 gggaaggtgcaatgagtagg gagggtcatc ctccatcctg ggctacatga agcgggaatg 7620 aagagtcaggcaaaaagaaa gtgagagctt gtggcaatga gaagtatatt atgtaaggga 7680 ctagggtgtgggtcaggtta agtttgaggg caaatgcttg aatgatccct ttaaaggaat 7740 gggtgggaagtggggagccc agtttgccgg gagggagaga tgcctcgaag ttcttatctc 7800 tggccactggcttgggccat ctgagtgtgg catctacttc taatgcctag gcagcaacct 7860 ttgctgtgtcatctccctta cacaaggttg gaagcaggga gaccggtcag gaagcctttg 7920 gtgtaacccatgttattgta atattcattc atttactcaa cagatgttta ttgtgcacct 7980 actatgtgctgaggccatgg caggcaggct ctggggatgt ggctgagaac aggacagagc 8040 ccctggtccttgatatcctc aaggatgctc cctcctggag gccattaggt tcctgttcca 8100 tggtgttctgctggaaccct ccggtcccag agtgtgcagg agcctcccct cctggcaaag 8160 ggtcttctctcatggcacaa gggctgcagt acagccagtc agtggctcct ggttcctcaa 8220 actcagtgagcacttgcctg cccttcgtgc tgcccctcag cttgggatgg cctgagtcaa 8280 gaccagccaggagctccagg cttcatgacc cctttctttc ccccagggag gccccgtctg 8340 gcccctccccagaatgtgac gctgctctcc cagaacttca gcgtgtacct gacatggctc 8400 ccagggcttggcaaccccca ggatgtgacc tattttgtgg cctatcagag gtagaggaga 8460 ctctctcggctggtggatgg gaagactgag ggggtgggtg ggggcttgga ggggcttctc 8520 tgggacagctgcacccagtg tgggcagcac tggctagctc tctgggccct acgggagatg 8580 gcatgtggccggcatttgga gaggggcttt tgataaaggt ctggaggtgg ggaagatgtt 8640 gaatgaagagcagtgtacag gtgaccagtc tgccggggcg ggggtaagtc tttgaggaaa 8700 gttggtgtggggcatggatg tagctgtggg ggccagagga tgaaattctc aagtggctgg 8760 atgaggtgcttggagctgtc ccagctgatc agtgaggcaa ctaggtacac ggcagaggag 8820 ctgttacctgggcaattagg catccctcaa tgatcacact ttttttctct tttttttttt 8880 tttttgagacagagtcttgg tctgtcaccc aagctggagt gcagtggctt gatctcggct 8940 cactgcaacctccacctcct gggttcaagt gattctcctg cctcagcctc cagagtagct 9000 gggattacaggcatatgcca ccacatctgg ctaatttttg tatttttaat acagacgagg 9060 tttctccatgttgcccacgc tggtctcgaa ctcctgagct caggtgatcc acccacctca 9120 gcctcccaaagtgttgggat tacaggcgta agccaccgcg cttggccaaa tggtcacact 9180 tttcccgatgggatcattct caatttggaa gcccaggcag ccacagcgaa tccagagaaa 9240 tctgacaatggaagcagatc caccatcttc gaacatagat gggaatcgtt cagagttctt 9300 tagcaggacagtgagatgat agaagcagaa gctcgggagg attcacctgg agttggtgag 9360 gaggggaaagcaggaagagg aggggaccca ccgtgtcctc aggacccgtc ctgtgccagg 9420 ccaagtgctaagggccctac gtgaatattt cacttccttc tcccaatgtg accaggcagg 9480 ctctgtgttttccccattct agaggtgagg gggattgagc actgtgtcaa cacatgtaat 9540 gaacttaatctcacagcagc tctctgagga caagttcagt acgcctcttt acagaggagg 9600 agactgaagcaccaagggtg catgttgctc aaagtcacac agctgggcgt agtatggctg 9660 gaataaatttattaaggagt tgaaagtcta tcctctagga ccaagcatgg tggcttacat 9720 ctgtaatcccagcactttgg gaggccgagg tgggtgggga gattgcttga gtccaagagt 9780 tccacaccatcctgggtaac atggtgaaac cctgtctcta caaaaaaaaa aaatacaaaa 9840 aattagtgaagtgtagtagc atgtgcctgt gttcccagct acttgggagg ctgaggtggg 9900 aaggatcacttgagcccagg agatggaggt tgcagtaaca aagatcacac cactgcactc 9960 caacataacaacagagcaag atcaaaaggg tttttagctc ccactgaacg ccncgtcata 10020 nccttaggtnnnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 10080 nnnnnnnnnnnnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnng aacaacagag 10140 caagatcctaaaaagaaaga aagtctatcc tctgaacttc tatgatattt ttcatgtctt 10200 ttatacattagaatggtgat attctaatta tataattttt ttcatttgtt agttggaatt 10260 attttataaagagatgtatc ctctcatctg gtatttgata tccagtcata ctattcaaat 10320 aggcaagagaggataaatgc ttaatttttt tcctttatca attttcaaga taatgaattg 10380 gttccttatcatctcccaaa ggtgattgct agtttattat tatcattatg aactcaggca 10440 tttaaacacatttggtggtt tcagtctatt gcgacgtact ctgctcattg aagcttgaat 10500 tgcctcatctctgtccagtg ggagtctcat caagtttgct cctgagtcct tttaacttga 10560 ccctagtggtcaagttaaat ctttccagat ttaacagata cctttccagc tgtccattac 10620 gacaagatgttccaggtccc tctggtacaa ttcctgacct aaaacctgca gtcagccatt 10680 tctccatttagtaagaaatg gttataaaga ctataatctg catgctagct atgctgatca 10740 ctacttagctattgcttttg gtgttttcag tgaacagagt gatgtgtgta taccacatag 10800 acacacacatgtacatactt ttttttttta gacagagctt cactctgtca cccaggccag 10860 agtgcagtggcatgatctcg gctcactgca acctccacct cctgggttca agagattatc 10920 ctgcctcagcctactaagta gttgggatta caggcgccca ccaccatacc cggctaattt 10980 ttgtatttttagtagagacg gggtttcacc atgttggcca ggctggtgtc gaactcctga 11040 cctcaagtgatctgcccccc tcggcctccc aaaatgctgg gattacaggc atgagccatc 11100 gcacccagcctacatgtaca taatttttaa gataaaatgc ctaatgagtt atacgggtgc 11160 ttcccatctaaatttagttc cttaggattt ttacctgact tctatggtac atctatattt 11220 tctttctttcacactgagaa tcctgtttct caaggacagg ggacatgata gaactagaat 11280 gacccataattactcatttt ctttatccca aaacatacat acttgcctct taatagtttc 11340 ttgctcttttcgcccaaagg gtttgtgatg gtcaatatta ggtgtcaact taattgggtt 11400 gaaggatgcctagatggctg ttaaagtttt gtttctgggg gtgtctgtga gggtgttgcc 11460 agaggagactgacatttgag tcagtggact gggaatggaa gactcgtcct cactcagtgt 11520 gggtgggcacaacccaactg gctgccaggc tggctggaaa gcaggtggca gatggtggga 11580 tagcttcacttgctgggtct tccagcttcc ttctttctcc cgtgcgggat gcttccttct 11640 gctcctcctgcccttgaaca tcacactccg ggttttttgg cctttagact cttggactta 11700 agttagtggtttgctggggg ctctcggatc tttggtcaca gactgaaggc tgcactttca 11760 gcttccctggttttgagggt ttcagattcg gactgagtca ctatggcttc tttctttccc 11820 accttgctgacggcctatcg tgggacttcg ccttgtgatc gtgtgagcca attctcctta 11880 ataaactccctttcatatat acgtataacc tattagttct gttcctctgg agaaccctga 11940 ctaataaagggttgttgctt tttctttaaa atctagtaat tttatttgac tgtgtgttgg 12000 tattgctcattcattctgag ttgatatttt taggcactca atattctcac ttaatacatg 12060 gttccaaggcatttttattt taggaaggtt ttcttaaatt atagttttag tatttgttct 12120 attctcttgttttgattttc ttctttaggg actcatatca cttgtatgtt ggatcttctt 12180 tttctgtgttcagtatttgt cttttgggca cagagactca cacctataat tccaagactt 12240 tgtgaggcataggtaggagg atcgcttgag cccaggagtt tgagaccagc ctgggcaaca 12300 tggtgaggccctgtctcaaa ttaaagaaaa aggagagaat acttgtcttt ttctttcaaa 12360 tgccttttatctgtctgtct atctactatt ctgctctcta aatgaaatag gtttcactct 12420 tgagtttttaaaaaactgtg tgcttccatg tgtgagatta ttcaacatct tatttgtaat 12480 ctttctcttggttacattta tttttcctga aaactctagt ctgcttttag ctgacatgtt 12540 tgtagctaagagcgcacatt tcttatcata gcttgccgtg ctgaattaat tccaattttc 12600 ttttaaaaccaacattattg agttaaaatg tatatagaat aaactgttcc cattttaaag 12660 tatacaatttgatgagtttt gacaaaagtg ggcacccacg tacccaccac cacaatcaag 12720 atgtaagacgttctctatca ccccagaaag ttccctcatc cactttgcat tcaggcctcc 12780 agatctaggcaaccacagat ctgctttctg acactgtgga ttaaactttg cctgttccag 12840 aatttcatataaatggatgt gtatagtatg taccctttcg tgtctggctc ctttccctca 12900 gcataatgtttctgaaattc acccacattg ttacatgtat cagtagttaa ttccttttta 12960 ttgctgagtagtaatgccat tgtatgacta tgtatgacat ttgttaatcc attttcccgt 13020 cagtggatatttgggttgct tccagttctg ggcaggtatt catttgctag ggctgccata 13080 tgcttgccctctggcctccc aaaatttgtg tccttttcat atgcaaaata cattcacccc 13140 ctcccaacagccccaaaact ctcttttttt tttttttttg aaacagagtt ttgctcttgt 13200 tgcccaagctggagtgcaat ggtgtgatct cggctcactg caacctctgc ctcccgggtt 13260 caagagattctcctgcctca gcctcctgag tagctgggat tacaggcatg cgccaccacg 13320 cctggctaattttttatatt tttagtagaa atggggtttc accgtgttag ccaggctggt 13380 cttgaactcctgacctcagg tgatccgcct gccttggcct cccaaagggc tgggattaca 13440 ggcatgagctactgcacctg gctagcccca aaactcttaa cccatttcag catctactct 13500 aagtccaaagtctcatctaa atcaggtatg ggtgtgactg gaggtgttac tcatcctgag 13560 gccaaattcctctccactta tgaacctgtg aaaccagaca ggttatgtgc tttgaaaata 13620 aagtgatgggacatgcatgg gatagacttt cccattccaa aagagaaaaa taggaaagaa 13680 ggaaagagtgacaggtccca agcaagtcta aaacctcgca gggcaaattc cattagattt 13740 taagtttcaagaatagccct ctttggctca gtgctctgcc ctttgggccc actggggcgg 13800 cagccctatcccctttgccc tgggtggtga ccctaccctc gagtcactgg ttagcagcag 13860 cctagcctgctgaaactaag gaggggacag tgttgcctcc aggtctttgg tggcagtgac 13920 aaccctgctgatctctgaat catcttccag gaaatttttc cctatacttg aaggatattg 13980 cgtgttcacagccaaatagc tccagctctt gtccctttct ttagaatccc agaagtccaa 14040 cagccttccttcattctgtc ccatctctgt cccctttagt caaagctgga agtgcctctg 14100 ctggtataatcccatcagta tgtctaattt ctgcttaaat ggctgattaa gtctatgagt 14160 tgcacctctgatctctttat caaaaggttg ttctagccac aaccttagtg tcctccccag 14220 aacatgctttctcatttttt tttttgcaat gtggataggc tgaaaatttt ccaaagcttc 14280 aagttctagttccttttggc ttaccaattc ttttcatata tctcttctct cacattttac 14340 tataagcagtaagaagaaac caggttgtac cttcagcact ttgcttagaa atctcttctg 14400 ctaagcatccaagtttatgt cttttaaatt atctttttgt tatttatttt atattatcat 14460 ttttgagatggctagccaat gatcttttaa cttctaattt ctgcaaaaca ctagaagaca 14520 attcaaccagttctttgcca ctttataaca aggatcacct ttcctccagt ttccaataac 14580 acattcctcttttccacctg agacctcacc agaatcacct ttaatgtcta tattcctacc 14640 aatagtctttttaaggcaat ataggctttc tctaacatgc acttcaaact tcaagattct 14700 acccattatgcaattccaaa gccacttcca catttttagg tattgattac ctcagcacct 14760 catttctggtgcccaaatct gcactggttt gctagggctg ccataacaaa gtacgacagt 14820 ctgggtaaacaacagaattt tattttctca aaattctgga ggttggaagt ccaaggtcaa 14880 ggcgttgctaggtttagttt ctcctgaagc ctctctcctt ggctagcaga tggctgcctt 14940 cttgctgtgtcctcacgtgg ctttttctct gtgtgtgttc actctggtat ctcttcctct 15000 tcttacaagtacaccagtcc tactggatta gggccccagc cttattactt catttaacca 15060 taattacctctttaaagctc ttatctcaaa acacaatacc actggggatg aggtcttcaa 15120 catatgaattttgggggaac tcaattcgtc cataataggg ctattatgaa ttaagctgct 15180 gtgaacattcatgtacaagt ctttgtgtgg atatgttttc atttctctta gataaagatc 15240 taggagtatcagcctgggca acatagtgag accccatctt tacaaaaaat tttcaaaatt 15300 agccaggcatggtggcgtac acctgtagcc ctgccatctc aggaggctga ggtgggagga 15360 tcccttgagcccaggggttt tagactgcag tgaactatga ttgcaccact gcaccccagc 15420 ctgggtgacagagtgagact ctgtctctaa aaaaaagaga gagaggggag gaaggaaaga 15480 agaaagagagggagggaagg agggagggag ggagggagaa gaaaaatgga tctagggtta 15540 agatttaggagattaggtaa tgaatgtgta ctattacagg gaactgtcga gctgtttcca 15600 aagtgactgtaccattgttc attgccacca acaatacatg agagttctag ttactccatg 15660 tgcttgttacacttagtatt atcagtcttt ttcattttaa ccattctagt gagtatgtag 15720 tagtattttattatggcttt aatttacaac tccctaatga tgaatgatgt tgaacatctt 15780 ttcatgtgcttattggccat tcatatatct tttgtgaagt gactattcaa atatttttcc 15840 actttttattaggtcattta ttttcttatt attgagttat ctatgaatac aaatccttta 15900 tcagtgtatgtattgtgatt tttttcccca gtggctggcc ttttcatttt cgttaggctt 15960 ttttggtgggtttttttttt tttttttgga agagaaaaat attttaattt gataaaatcc 16020 agtatatcaggtgttataga ctgaattata ctctacccca caaattcata tgttgaagcc 16080 ctaacctctaagtgactatt tggagatgag cctttaagga ggtaattaaa gtaaaatgag 16140 atcataagggtgggccctaa tctaatagga ctggtgtctt tataagaaga ggaagacacc 16200 aagagcgcatgcacacagaa gaacggcctt gtgaggacac agcaagatga cggccatctg 16260 caagccaaggagagaggcct cagtagaaac caaacctgct gatgccttga tcttggactt 16320 ccagcctccagatttctgtt gctgaagcca ccctgcctgt ggtgtcttac catggcagcc 16380 ctcacagactaatatatcag atttttttcc ttcaacagtt aacgcttttg gtgtcctaag 16440 caatattcgcctgacccagg gtcatgaaga tttttcttct atgctttctt ctggaagttc 16500 tataattttagcttttacat atttttttaa ctttccttct tcttgccttc tgtttctttt 16560 aaggcatcatctattgtgtt aatttgttct tgtattcctt ctgatttatt cttcacttct 16620 gaaatgaattttgcttttta aaaatatata taattctttt ctgtgtctga gtttttctaa 16680 ttaggttttatgtggttttt tcttgtcctg catcactttt tactgtcttt tgcccatttt 16740 gaagtatcaggttccagttt tgatctgttc atggatatgt ttttgtgaca tgtttcttct 16800 ggcttcttatcatttattgc ttagcttatt aatttctatt ctttcttatt ttctattata 16860 agtatttaaagctatatgtt ttcctctaag tattacttag ctgtcttata cgttttcatt 16920 tgtgttatttggtgatcatt cactttcagc tatttattaa tttccattat aattctttca 16980 tctatgggttgttttaaaaa atatttttaa ggccaggtgt ggtgactcac atctgtaatc 17040 acagcacttagggaggctga ggtgggagga ttgcttgagg ccagaagttt gagaccggcc 17100 taggcaacaaagtgagaccc cctctctaca gaatattttt ttaaaattag ctgggccagg 17160 cgtggtggctcatcccagca cctgtaatac cagcactttg ggaggccaag gcagatggat 17220 cacctgaggtcaggagttcg agaccagcct gggcaacatg gtaaaacccc atctctacta 17280 aaatataaaaattagccagg tgtggtgata ggtgcctgta atcccagcta cttgggaggc 17340 tgaggcaggagaattctttg aacccaggag gaggagtttg cagtgagccg agattgcacc 17400 actgcactccagcctggatg acagagcgag actctgtctc aaaaaaaaaa agaaaagaaa 17460 attagctgggtgtagtggca ggtacctgtg gtcccagtga ctcagagact gaggcaggag 17520 gatcacctgagcccaggagt agaggctgca gtgagctatg tttgtgccac tgcactccag 17580 cctgtgcaacagagcaagac gctgtctcaa aaaatatata tttttttaaa ttttcaaact 17640 tcctttagttctctttttgt tattaacttt taactgaatg ttttgcaatc agaagaaata 17700 ctttatgagatacctattct ttaaaatttc ttaagaattg ctttgtgtta atattttgtt 17760 aatagttcacatgtggttca accaatttgt ttagttagtt ctgtatatgt tcattagacc 17820 aacttgataactgtgttgtt ctttatttat ttatgtattt atttttcttt gtctattcat 17880 caattgctgggtgagatgta ttaaaatttc ttgttgtaag tgtggctgtt cactttctac 17940 ctgtagtttgtctgtttgct ttatagaggg tgaagttgtt tagtaggcac acataagtta 18000 gaatttttctgtcttcctgg tgaatggaat catttatcat tatctaatgt tcttttcatc 18060 tttagtattgctttggactt ggaagtctgt attttgtctc ctgttaatat aactacactg 18120 gttcctttggtgtgaatatt tgcatagtat aacattttcc atgaagaaac aaaacagagg 18180 aattggttctttctcaaaat ctgatctttg tgtcagcccc catctcagcc ttctccattc 18240 atccttggtcactccccaaa cccaggagca atccttgatt ctccttttcc ccacattcta 18300 catccaatccgttagcaagt tctattagtt ctattattac ctccaaaata gatattgaat 18360 ccagccctttctcactgtct ccaccatcat cctgtctcac atccctacca tggcctcctt 18420 gctggttgaccagagtgatc ttgtaaaaac atgttaggcc aggcacggtg gctcctgcct 18480 gtaatcccaacactttggga ggccaagcgg gtgggtcacc tgaggtcagg agttggagac 18540 cagcctggccgacatggtga aaccctgtct ctactaaaaa tacaaaatta gccaggtgtg 18600 gttatgctggcctgtaatcc catctactcg ggaggctgag gcaggagaat cacttgaacc 18660 caggaggcggaggttgcagt gagccaagat catgccactg caccccagcc tgggcaacag 18720 aacaagactccatctcaaaa aataaaaatt aaaataaaat gttaggctcc ctgggtctct 18780 ggcttagtccatttgtactg ctttaacaaa ataccttaga atggtgtaat tctaataatt 18840 gctattaataaataatagca attaataaat aatagcaatt tccttctcac agttctagag 18900 gctgggaagttcagggtcaa ggtggcacct gactccgttc tggtaagggc ggctctctgc 18960 ttccaagatggtgccttctc gctgcgtctt cgcatagcgg aagggcaaac actgtgtcct 19020 cacgtggcagaagagataga agggccaggc agctctctga agtatccagg ttggagtcat 19080 ggacctgcatgttcccctct gacatccaca gagtacctat catggtcctt ggcatgcagc 19140 aggtggcccataaacgcctg aatgaacaaa catatagtaa tggtcgctag tactaggaat 19200 agcagccaccgcaacagtcc tgtgagggag gcattacaga tgaggaaact gaggtttagg 19260 ggcaaggacctgcccatggt cccaaagcta gggagggaca gggctgggat tcccactccc 19320 atccatctggctccagaacc tgagctcctg accaggctgt tcttatcctg tctcagccag 19380 tggctgcctgtctggacgga tggacctaaa gtcagtccag ccaaacagag ggaagcatga 19440 tcaactgttctctaagttcc ctgacccgga gaggctgagt ccatggccca agctctcctc 19500 tctcctcccccagctctccc acccgtagac ggtggcgcga agtggaagag tgtgcgggaa 19560 ccaaggagctgctatgttct atgatgtgcc tgaagaaaca ggacctgtac aacaagttca 19620 agggacgcgtgcggacggtt tctcccagct ccaagtcccc ctgggtggag tccgaatacc 19680 tggattacctttttgaaggt aggtctgtgg gtaagggact gagtggaagg ctgtccatcc 19740 catcggggagctgtgctcag tgctcagtgg ttctgttctc ctgaccatct gtctcccact 19800 tccccaaagcagagggcagc tccctgggcc aggccctttg agatggggtg tgggaccagc 19860 aacagcgagggaccatgtct ggtagcctgt cagggagtta ggggagctcc agccagcacc 19920 agcaatctcacgtgcaccct ctgctaacaa tgttcattat tttcagttga gcaccatttt 19980 ggtcatggactacacaaggc actttatatg cttattccta tttttttatg ttcagcttct 20040 ctccttaaaaacaatgttta aaaccaattc tgggccaggc gtggtggctc acgcctgtaa 20100 tcccagcactttgggaggcc aaggcaggtg gatcacctga ggtcaggagt ttgagaccac 20160 cctggccaacatggcaaaac cccgtcttta ctaaaaatac aaaaattagc caggcttggt 20220 ggcaggcacctgtaatccca gctactcggg aggctgaggc aggagaatcg cttgaaccca 20280 ggaggcggaggttgcagtga gccaagatca cgcccctgca ctccagcctg ggcgacagag 20340 cgtctcaaaagaaaaaaatt aataaacaaa gaaaaaaaaa caaattctgt ttgcaaaagt 20400 attttctatacactgtagaa atttgtgggg tgtggggggg taaagatgat agaaaaaaaa 20460 atgtcccatgcttactggca gaaatcatgt attgacattg ggtgaggagg gcactttttt 20520 tttttcagtctatttttaat cttcacagca aacttgtgag gttcatttcc atcaacctga 20580 gactcacagaagctaagaaa cttgataccg ctagtaacca gtggacttga taccgctagt 20640 aaccggtggacatagatgtg aactggatct ttctgacctc gggcagggcc gggtaacaag 20700 gggaggataaatgcccagac agtgtcctca gagagctgag agctgtaact tgctgcccgg 20760 gcttctcacagtgttcaagg acaaaataag gctttaagag agaagaggga cagactgatt 20820 gcagggcagcaggaagagat ggtagagaag gaagaagaga tgattcgtgt ggaaagaagc 20880 tggctcggtggatggataaa agaagggaag gacagatggg taagaagaaa gggaggatgg 20940 aggggatggaggaggaagca atggaaaaat gggaaggaag gaggttggat ggaaggatag 21000 atgcctattaggaaggaaat atgtgtggat agagagatgg aggataggaa gtatgttagt 21060 caaggttctccagagaaact gaaccaatag gatatataca gatacactaa gaggaggcca 21120 gccgggcgcggtggctcaag cttgtaatcc cagcacttta ggaggccgag gcgggcggat 21180 cacgaggtcaggagatcaag accatcctgg ctaacacagt gaaaccccga ctctactaaa 21240 aatacaaaaaaaaattagtt gggcgtgatg atgtgcgcct gtagtcccag ctgctgggga 21300 ggctaaggcaggaggatggc gtgaacccag gaggcagagc ttgcagtgag ctgagatcgt 21360 gccactgcacttcagcctgg gtgacagagc aagactccgt ctcaaaataa ataaataaat 21420 aaataaaaagaggccagcca tggtggctca cacctgtaat ctgagcactt tgggaggccg 21480 aggcggatggatcatttgag atcaggagtt caagaccagc ctggccaaca tggtgaaacc 21540 ctgtctctactaaaaataca aaagttaccc gtgtgtggtg gcacacacct gtagtcccag 21600 ctactcaggaggctgaggca ggagaattgc ttgaacttgg gaagcagagg ttgcagtgag 21660 ctgagatcacgacactgcac tccagcctgg gtgacagagc aagactttgt ctcaaaaaaa 21720 aaaaatttataataagagga gatttattat gggaattggc tcatgcaatc acagacacaa 21780 aaatgtcccccagcatgcag tcatgggctg gacaaccagg aaagcttgtg gtgtgattct 21840 gtctgagtctgaaggcccaa ggccagggga gcagtggtgt aacccccagt ccgaggccac 21900 aggcccgacaatcagagggg ccactgatat aagtcccaga gtccaaatgc cggagaacag 21960 gaagctccaacgtccaagga caggagaagt tgatgtgcca gctcaggaag agagaatgtg 22020 aatgtgccattcctcctcca ttttttgttc tctttgggcc gtcagtggat tggatgatgc 22080 ctgcccacactggtgaggac agatcatcac caaatctgcc gattaaaatg ttaatctctt 22140 ctggaaaaatcctcacagat gggcccagaa ataatgtttt actgtctacc tgggtatccc 22200 ttagtgcagctaaattgaca cataaactta accatcacag gccaggcact gtggctcaca 22260 cctgtaatcccatcactttg ggaggccaag gtgggaagat cctttgagga tgaggtaggc 22320 agatcacttgagcctaggag ttcaagacca gcctaggcaa catagggaga cctcgtctct 22380 acaaaaaaaaaaaaaattta aattcgctgg gtacggtggt gggcacctgt ggtcccagct 22440 atctgggaggccaaggtagg aggatgactt gagcccagga ggtcaaggct gcagtgagcc 22500 atgattgttccattgaattc cagcctcggt gacagagcaa caccctgtct taaagaaaga 22560 aaaaatttaaccatcacaga aggcagaaga aaaggcagat gggtggatga gatgggtggg 22620 tagatagtatagaagaaaag cgggacatcc aggcagggaa ggaagggctg gagcgaagga 22680 gaagcaaggaaggaaggaag gagagacaag aaggaaggat gtgtagaaag gtggaagaga 22740 aaagaagaatggatgtatgg gaagaatgga tgagtaggtt agaaggctca ctggctagat 22800 aaaaggtgagaagtataaat gaataataag aaaggaggca taggaagaaa aaaatattgg 22860 ttagaaaggatgattgagaa gaaagggtgg ttgggaagga aggaaggaag gatggatgga 22920 tggatggatggatgggaagg aaaggaagga taagaaggca gacaggaagg ctctctggct 22980 agaagaatggcagacaaacc acaataattg ctgaatgggt aggaataaga cattagaaga 23040 ataaagggaaagacacaaag atatttaaaa tgttttcatt aattttttgc ctcctccctg 23100 aatttctcctgattcttcag ccccacatcc caagccaggg tgatccttcc tgcctttaca 23160 ctccctccacactttttctg ctctcatatg tggccgtggt cactttcttt tggtagtttg 23220 catatttcatttaccccaaa ctttcagctc ctgaaggtca ggatacaagg aggcctcatc 23280 tccgcattcccctcagctcc cttcctgaag cttgatacct agtcagtacc cagtggatgt 23340 ttcctaaacatgtaagtaat gacatcatga agaagccaca tgtttacctt gaccacaaac 23400 acagggcaaaggtgactagt gtggtcagag atccctgctg gctgggaatc agggaaggct 23460 gcatggaagaagtggcattt tagttagaac ttgaaaggtg gtgtatttag ttttctctgg 23520 ctgccatattccttgtcaca ttgccctctc catcttcaag ccactgggca aggctagaag 23580 gccctcaacagactatcggt aggaatgtgg aagttgaaga ctcagagtgc agaaagaaac 23640 aagtagcattttagagaaaa gctaaatccc ctccaagaat acctcaatca tcgtgaagag 23700 cctgttagtagacgcactaa cactcaaggc actgcttcac aaggtaagga acgtgtaatt 23760 gaaaacttgagaaaggaaga aacttgttct gtactggcag aaagcttagc agaattgtgt 23820 cctgcagtcatatgggacac agagcttgta aatgatgaat ttgaatgctt atccgagaag 23880 gtttccaaataaaatgtgga aggcacggcc tggtttcttc ctgcctctta tagtaaaatg 23940 caagaggagagagagaaaat gagggaagaa cttaaacaga aaggaaccag gacttgatga 24000 tttgggaggttctcaaccta tgcaaaaaac aataaaatta agagattgta gctgggcaca 24060 gtggctcatgcctgtaatcc cagcactttg agagtccgag gcgagcagat cacctgaggt 24120 caggagtttgagaccagcct ggccaatgtg gggaaactcc gtctctacta aaaatacaaa 24180 aattagctgggtgtggtggc gggcacctgt aatcccagct actcaggagg ctgaggtggg 24240 aggatcacttgaacccaaga ggcggaggtt gcagtgagcc aagatcatgc cactgcactc 24300 cagcctgggtgggtgacaga gcaagactcc atctcaaaaa aaaaaaaaaa aagagattgc 24360 tcccaaaagtgtgacataga gaaacagcca agtatgtgat tataccaaac ttcaggaaga 24420 taaaagatcaaagtactcag tcgctcaaaa ggctctttga agagattaag attataactc 24480 acagtccccttcaatcaaac caggggactt ctaggaagct gaacagcatt gtccctcagc 24540 catatcagctggagccaaaa gtagagaagg gcttatctga aaaaaggatc tgtggacctg 24600 gcttttatctaataatgcag tggattcccc catgacatcc ataggagacc cgtaaagttc 24660 ctgagacgtttacatccaca gaaacactgt tagcttggat taaatggaac acagagagta 24720 tgaaatcaaagaaggctgtt ggactctcca gtttctactg ttgagatgca gactggtaaa 24780 actacttagctgcaaacacc tgctaccttt agtgaaaagg aaggatatct cagacggtga 24840 aaccagaagctcaaagggca gtgctaagag cgaaagagaa ttcttcccag gccttgaaac 24900 ctaatggagttttcttggct ggattttcaa actgcattgg accatgacct gattgtccct 24960 ttcatgtccccatgcttgag ccagattgtc tgcaactgtt atcctgtgcc tgtcccacat 25020 tttatgttgggagcagaaaa ctttagtttt gctggcccac agatagagag aaactgtacc 25080 ccgagagttgtactgactgg actatgccca gagtctattt gactctgact tagatactgt 25140 tgatttgggaatttgagttg atgctgtaat gagatgagac tttgggggac attgggatgg 25200 agtgaatggattttgcattt gaaagagatg tgggttgggt aatcctagcc cacacctgta 25260 atcccagcactttgggaggc cgaggcaggc agatcacctg aggtcggcag ttcgagacca 25320 gcctgaccaccatggagaaa ccccatctct actaaaaata caaaattagc caagcatggt 25380 agcacatgcctataatccca gctactcggg aggctgaggc agtagaatcg cttgaacccg 25440 ggaggcagaggttgcggtga gccgagatca cgccattgca ctccagcctg ggcaacaaga 25500 gtgaaactccatctaaaaaa aaaaaaaaag aaagaaagag atgtggattt tgggtggggg 25560 acagagggaagaccatggta ggcagaatga tcctctaaag gtgctctgcc ctaatcccca 25620 gaagctaagaatatgttaga tgtcagtatt gcgtggcagt aggaatctta attaacgtta 25680 tagactgttatggtttgaat gtcccctcta aaactcctgt tgacatttaa tcatcattgt 25740 gattgcattaagaagtggcc ctgttaaaag gtgatttagt ccttaagaac gctgcccccg 25800 tgaatagattaaggtcagtc ttgcgggagt gtgtttatca agaatggatt gttaaaaagt 25860 gagttctggccaggggcagt ggcttatgcc actcagcact ttgcggggcc aagacttgaa 25920 gtcagttgtttgagaccagc ctggccaaca tggtgaaagt ctgtctctac taaaaaatac 25980 aaaaagtgtccgggagtggt ggcgggcgcc tgtaatccca gctgctcagg aggccgaagc 26040 aggaggatcgcatgaatccg ggaggcagag gttgcagtga gctgagatcg ccccgttgca 26100 ctccagcctgggtgatagag caagactctg tctcaaaaaa annnnnnnnn nnnnnnnnnn 26160 nnnnnnnnnnnnnnnnnnnn nnnnnnnnnn naaagaaaga aagaaaagaa aagaaaagtg 26220 agttctgccctctcttgctg gcttactctc accctctctt gcccttccac ctgccaccat 26280 gggatgacacagcacaaagg ccctcaccag atgccagtgc catgctcttg gacttccaag 26340 tctccagaaacatgagccaa atacacttct gttcattata aattacccag cctgtgatat 26400 tctgtaataacaacacaaaa tagactgaga catagatctt caaatagtga ggttatcctg 26460 gataatccagatgggcccaa tctaatccca tgagccttta aaactttctc cagatggagg 26520 cagaagagaagtggcagaag gggaagtcag agagatttga agcataaaca ggactccatg 26580 gtgccgtttctggtttgacg atggagtggt aacgtgatga aaaatgtggg tgccttccgg 26640 agctgagaggctcccactaa caatcggcca ggaaacaggg accacagccc tacagccaca 26700 aagaactaagttttgctgac aacccaaggg ggcttggaag tgtcttctcc cccatcggtt 26760 ccagatgtgagacccagagc gaaggaacca gctgagccca cctggacttc tgacctagag 26820 aactgtgagataataagttt gtatcatttt taaggcactg tgtgtgtggt aatttgttat 26880 gacagcaatagaaaatgaat ccagatgggc aggatctgcc aggccagtga catgtggagg 26940 gcacccaggcggatgggatg gcatgagaga aggcaggtca gcaatgagct tgcccaggtc 27000 acctctcctctctaagcctc agttttcctc tctatgaaat gagagtagtg atatctccct 27060 cccagggtcagtgcaaggct gaaataacag attataaggt gctaggtgca caagaagtgt 27120 ttgaaacatgctagttgctt ttccatttcc aagagagctc tctggtcttg ggggatggag 27180 gcagtgcggcccctcgggat tactgacagg tcctgctctg tttctgcagt ggagccggcc 27240 ccacctgtcctggtgctcac ccagacggag gagatcctga gtgccaatgc cacgtaccag 27300 ctgcccccctgcatgccccc actggatctg aagtatgagg tggcattctg gaaggagggg 27360 gccggaaacaaggtgggaag ctcctttcct gcccccaggc taggcccgct cctccacccc 27420 ttcttactcaggttcttctc accctcccag cctgctcctg cacccctcct ccaggaagtc 27480 ttccctgtacactcctgact tctggcagtc agccctaata aaatctgatc aaagtatgat 27540 gacctacaggaggcctgctt gccaagtcaa cagattcagt acagaaaaac tgaaaaatac 27600 agataagctctaagaagcag accaaaagta cccagagatg accgcacatc actctggtgt 27660 atatccaatttcagatttgt tttctgtgta tgcatgtgtg tatagctgca tttatttatg 27720 gcaagggctggcagactttc ccgaagaagg ccagatagtc gatatgtttg gcttcatggg 27780 ccgtatgttcgctcaggact actcaacgct gcagttatag cacaaaagga gccgtagcct 27840 atacgtaaatgaatgggcat cgctgggttc cagtaaaact gtttacaggc caggtgcggt 27900 ggctcatgcctgtaatctca gtactttggg aggccgaggt ggtgggagga ttaccttagc 27960 ccaggagttcaagaccagcc tggggaacat ggtgaaacat tatccctaca aaaaaaaaaa 28020 aagctgggtgtggtgatgca tgcttgtggt cccagctgct tgggatgctg aggcaggagg 28080 atcgctcgagcccaggaagc aaggccacag tgagccatga tcgcaccact gcactttagt 28140 ctgggcaacagagtgagacc ttgtctcaaa aaaaacaaaa aataaaactt tttacataaa 28200 caagtggccaaccagacttg gtccctgggc ctctgctctt gaatgttctt gcttccacta 28260 aagtaacattcacactcccg atttttgcat actctgggtt ctggggaata tagatccgaa 28320 tccagcgtggttcctgcctt caagaacctc acaaatattc tagaccagca ctgcccaata 28380 gaaagaaatataatgcaagc cacatgtgca gttttaagtg ttccatgtta aattaagtaa 28440 aaagagacgggtaaatcgaa ttttaataac agattttact tcatccaatt gaatggtatc 28500 atttcaatgagcaattctga tagtgattga gatcttttac attctttttc actacgtctt 28560 taaaatctgatgtgtgtttt gtacttggaa cacttctcag tgtggaccag atgcatttca 28620 catactcagtagtcacgcgt ggccagtgcc ttccatacca cacagtgcag catctgtaga 28680 ggtttcctccactgctgata gactaggaga ccccaagatg gaaagcctga agaatctgct 28740 ccttgaagtagggaccttaa tggggtgcac gccagggcga ccccaagtgg taggctgctt 28800 ttgaaccatggctatcccta cctctagact cagctgaaaa gaactcaggt agtcttggga 28860 agtgcttcctcaatgcttaa actttaatgc aggaaaagaa tagaaagttc aggcaaggag 28920 ggaggatcacttgaggctgg gagttcgaga ccagcctggg caacagcaag accttgccta 28980 tacaaaaaataattttaaaa aattacccag gtatggtggt gtggatctgt agtccctagt 29040 tacttggagagctgaggtag gaggatcgct tgagcccagg agtttgaggc tgcagtgagc 29100 tgtgatcacaccactgcact ttggcctggg tgacagaacc aaaccctatc ccctacaaaa 29160 aaacaaaaaaaaaaaacaaa aaaaaacacc ctaccatgtc tgccaacccc actctgtcct 29220 ggctgtgtgaaaccagtccc cacagcagct ctgccactct ctgcttcttt tccaaacaga 29280 ccctatttccagtcactccc catggccagc cagtccagat cactctccag ccagctgcca 29340 gcgaacaccactgcctcagt gccagaacca tctacacgtt cagtgtcccg aaatacagca 29400 agttctctaagcccacctgc ttcttgctgg aggtcccagg tgggtatcaa gtggtgcaga 29460 aggagaaactttccctctgg gccttgggag cttcgtgaca cagtggttaa gaacatgagc 29520 ctagagatagactcgcctgg attaaaacca cactcattgt gtgtctttgg gcagcttaca 29580 taatgccccgaaccttggtt tgcacagtct gcaggatggg tttattcttg tgaggattaa 29640 atagggtcatgtatgtgaag cactcggcac aggtgcagtt gtagacaaga gccattgttg 29700 tttctctcattgttattttt ccttccttag aagccaactg ggctttcctg gtgctgccat 29760 cgcttctgatactgctgtta gtaattgccg cagggggtgt gatctggaag accctcatgg 29820 ggaacccctggtttcagcgg gcaaagatgc cacgggccct ggtatagcaa atctgggggt 29880 gtgcggcaggtggggagggg ttgagagtaa gggagtgggg ctggagctat gagttgttca 29940 gatagaatatcaagatggtc cagactcttg gaccaaaaca tctatctttg tgtctgaatt 30000 tccaccattagtaatgcatt catttagtcc tgaataaaat ggcaaacagg ccctggaggg 30060 agcagtgccttaagttcctt tgagataaat aacttcacct ctgctaagga tgtgtcagct 30120 gctgagagcagagcccctgg ccttggacct caggagagac actcaaaagg ggaggagagg 30180 aggcaccaaaggggacatct taaaagagtt ccaattttta gttcacactt taacccagga 30240 taagctgtgtcctggctgac cttggagttt cttccctggt ctgctgggtc tctcccttag 30300 aacctaggggcgagctgggg caggggaagc ccaggaggtg atataggtcg gccctgttca 30360 gatgagggctggcaggggca gcttgggcat atgcgaggct ccgatgggca tgggggcttt 30420 gaggatggattctgagtgtc cctgcatcgt ggcagggtgg caaagggagc atttccaaat 30480 ttcctggctccaggatctgt gggagaatcc cactaactgt cagggtgaca acctcgggta 30540 gacatgtctgtgccctgccc cgtgccctca gccttcctgt taagagcaca ccagctggat 30600 ttgcaactcccagcgcctgc acccaatggg ctttctctgg cctctggagc ccacattgcc 30660 cctgcatgtggcaggctgca agtgtcacag ccaccagctc ttccattcct caacaatgac 30720 tgtgggtaaatagcccagga gcgtccccct cctgggatgg ttctgaggtg cgtgtgccca 30780 gtggctccctgagttgccag caggattaag tgccagtagc cctagtggtc agctgcttga 30840 taacaccctgcttcctggct gctcccccag tcccatctgg tgtgttctgg gatcatctcc 30900 caaagaaactgcttacactt gaagccttgt ctgaggtctg tttctagggg aattcagatg 30960 acgataattatgcttcagga aagcctaaat tttctgcttt tctctcccct acccaaatca 31020 ggacttttctggacacacac accctgtggc aacctttcag cccagcagac cagagtccgt 31080 gaatgacttgttcctctgtc cccaaaagga actgaccaga ggggtcaggc cgacgcctcg 31140 agtcagggccccagccaccc aacagacaag atggaagaag gaccttgcag aggacgaaga 31200 ggaggaggatgaggaggaca cagaagatgg cgtcagcttc cagccctaca ttgaaccacc 31260 ttctttcctggggcaagagc accaggctcc agggcactcg gaggctggtg gggtggactc 31320 agggaggcccagggctcctc tggtcccaag cgaaggctcc tctgcttggg attcttcaga 31380 cagaagctgggccagcactg tggactcctc ctgggacagg gctgggtcct ctggctattt 31440 ggctgagaaggggccaggcc aagggccggg tggggatggg caccaagaat ctctcccacc 31500 acctgaattctccaaggact cgggtttcct ggaagagctc ccagaagata acctctcctc 31560 ctgggccacctggggcacct taccaccgga gccgaatctg gtccctgggg gacccccagt 31620 ttctcttcagacactgacct tctgctggga aagcagccct gaggaggaag aggaggcgag 31680 ggaatcagaaattgaggaca gcgatgcggg cagctggggg gctgagagca cccagaggac 31740 cgaggacaggggccggacat tggggcatta catggccagg tgagctgtcc cccgacatcc 31800 caccgaatctgatgctgctg ctgcctttgc aaggactact gggcttccca agaaactcaa 31860 gagcctccgtacctcccctg ggcggcggag gggcattgca cttccgggaa gcccacctag 31920 cggctgtttgcctgtcgggc tgagcaataa gatgcccctc cctcctgtga cccgccctct 31980 ttaggctgagctataagagg ggtggacaca gggtgggctg aggtcagagg ttggtggggt 32040 gtcatcacccccattgtccc tagggtgaca ggccaggggg aaaaattatc cccggacaac 32100 atgaaacaggtgaggtcagg tcactgcgga catcaagggc ggacaccacc aaggggccct 32160 ctggaacttgagaccactgg aggcacacct gctatacctc atgcctttcc cagcagccac 32220 tgaactcccccatcccaggg ctcagcctcc tgattcatgg gtcccctagt taggcccaga 32280 taaaaatccagttggctgag ggttttggat gggaagggaa gggtggctgt cctcaaatcc 32340 tggtctttggagtcatggca ctgtacggtt ttagtgtcag acagaccggg gttcaaatcc 32400 cagctctgctcttcactggt tgtatgatct tggggaagac atcttccttc tctgcctcgg 32460 cttcctcatctgcagctacg cctgggtgtg gtgagggttc taggggatct cagatgtgtg 32520 tagcacggagcctgctgtgt cctgggtgct ctctacgtgg tggccggtag aattctccat 32580 ctatccaggctccaggagac ccctgggcat ctcccacctg tggcccctaa acccagagtg 32640 actgagagcacttaccattc agcttgtctc atccccagtc tacctccttc cttctaccct 32700 cactgcctcccagtcaggag agtgagctct cagaagccag agccccaccc aaggggaccc 32760 tggtctctccgccttcacct agcaatggga accctgcttc ccaggggagg aaccaactgc 32820 tccaccttctagggacccag tttgttggag taggacagta acatggcagg aatcggactt 32880 ctgggcctgtaatcccagtt tggatggcac gttagactct tggttgaccg ttgtggtcct 32940 tagaagtcccattctccctt ccagttatga gaaaccaatg ccttctagat tcaggtgact 33000 atccttacctgggggtgctg atgcatcctc agttaaccta cacccacctg aatatagatg 33060 agcgtagctgagttttcacc cgtaggaccg aagtgttttg tggtggagta tctgaacaac 33120 cttggctctgtggccattca acctgccagg actaacattt ctggatttgt gaagaaggga 33180 tcttcaaagccattgaaccc acagagctgt gttgctttaa agccaccaca agggtacagc 33240 attaaatggcagaactggaa aagcttctta gggcatctca tccagggatt ctcaaaccat 33300 gtcccccagaggccttgggc tgcagttgca gggggcgcca tggggctata ggagcctccc 33360 actttcaccagagcagcctc actgtgccct gattcacaca ctgtggcttt ccacgtgagg 33420 ttttgtttagagggatccac tactcaagaa aaagttagca aaccactcct tttgttgcaa 33480 aggagctgaggtcaagggtg gcaaaggcac ttgtccaagg tcgcccagca gtgctgctct 33540 gatgacttgtgcacatcccc aagggtaaga gcttcgatct ctgcacagcc gggccaacct 33600 ctgaccccttgtccatgtca gtaaaatatg aaggtcacag ccaggatttc taagggtcag 33660 gaggccttcaccgctgctgg ggcacacaca cacacatgca tacacacata cgacacacac 33720 ctgtgtctccccaggggttt tccctgcagt gaggcttgtc cagatgattg agcccaggag 33780 aggaagaacaaacaaactac ggagctgggg agggctgtgg cttggggcca gctcccaggg 33840 aaattcccagacctgtaccg atgttctctc tggcaccagc cgagctgctt cgtggaggta 33900 acttcaaaaaagtaaaagct atcatcagca tcatcttaga cttgtatgaa ataaccactc 33960 cgtttctattcttaaacctt accatttttg ttttgttttg tttttttgag tcggagtttt 34020 gttcttgttgcctaggctgg agtgcagtgg tgcgatctcg gctcactgca acctccacct 34080 cccgggttcaagtgattctc ctgcctcagc ctcccaagta gctgggatta caggcacccg 34140 ccaccacacctggctaattt ttttgtattt ttagtagaga tggggtttca ccatgttggc 34200 caggctggtctcgaactcct gacctcaggt gatccgcccg cctcggcctc ccaaagtgct 34260 gggattacaggcgtgagcca ccgcgcccag ccaaacctta ctattttttt aaagaatttt 34320 ttccagagtttaatttctga catagcttaa gttttccagt aactctaaac tccatctcct 34380 ttatcgtcattaagtcattc acaaaaagcc aggagaagca tttggaaagg gcatgataat 34440 cagtataata34450 4 520 PRT Homo sapiens 4 Met Ala Gly Pro Glu Arg Trp Gly Pro LeuLeu Leu Cys Leu Leu Gln 1 5 10 15 Ala Ala Pro Gly Arg Pro Arg Leu AlaPro Pro Gln Asn Ala Thr Leu 20 25 30 Leu Ser Gln Asn Phe Ser Val Tyr LeuThr Trp Leu Pro Gly Leu Gly 35 40 45 Asn Pro Gln Asp Val Thr Tyr Phe ValAla Tyr Gln Ser Ser Pro Thr 50 55 60 Arg Arg Arg Trp Arg Glu Val Glu GluCys Ala Gly Thr Lys Glu Leu 65 70 75 80 Leu Cys Ser Met Met Cys Leu LysLys Gln Asp Leu Tyr Asn Lys Phe 85 90 95 Lys Gly Arg Val Arg Thr Val SerPro Ser Ser Lys Ser Pro Trp Val 100 105 110 Glu Ser Glu Tyr Leu Asp TyrLeu Phe Glu Val Glu Pro Ala Pro Pro 115 120 125 Val Leu Val Leu Thr GlnThr Glu Glu Ile Leu Ser Ala Asn Ala Thr 130 135 140 Tyr Gln Leu Pro ProCys Met Pro Pro Leu Asp Leu Lys Tyr Glu Val 145 150 155 160 Ala Phe TrpLys Glu Gly Ala Gly Asn Lys Thr Leu Phe Pro Val Thr 165 170 175 Pro HisGly Gln Pro Val Gln Ile Thr Leu Gln Pro Ala Ala Ser Glu 180 185 190 HisHis Cys Leu Ser Ala Arg Thr Ile Tyr Thr Phe Ser Val Pro Lys 195 200 205Tyr Ser Lys Phe Ser Lys Pro Thr Cys Phe Leu Leu Glu Val Pro Glu 210 215220 Ala Asn Trp Ala Phe Leu Val Leu Pro Ser Leu Leu Ile Leu Leu Leu 225230 235 240 Val Ile Ala Ala Gly Gly Val Ile Trp Lys Thr Leu Met Gly AsnPro 245 250 255 Trp Phe Gln Arg Ala Lys Met Pro Arg Ala Leu Asp Phe SerGly His 260 265 270 Thr His Pro Val Ala Thr Phe Gln Pro Ser Arg Pro GluSer Val Asn 275 280 285 Asp Leu Phe Leu Cys Pro Gln Lys Glu Leu Thr ArgGly Val Arg Pro 290 295 300 Thr Pro Arg Val Arg Ala Pro Ala Thr Gln GlnThr Arg Trp Lys Lys 305 310 315 320 Asp Leu Ala Glu Asp Glu Glu Glu GluAsp Glu Glu Asp Thr Glu Asp 325 330 335 Gly Val Ser Phe Gln Pro Tyr IleGlu Pro Pro Ser Phe Leu Gly Gln 340 345 350 Glu His Gln Ala Pro Gly HisSer Glu Ala Gly Gly Val Asp Ser Gly 355 360 365 Arg Pro Arg Ala Pro LeuVal Pro Ser Glu Gly Ser Ser Ala Trp Asp 370 375 380 Ser Ser Asp Arg SerTrp Ala Ser Thr Val Asp Ser Ser Trp Asp Arg 385 390 395 400 Ala Gly SerSer Gly Tyr Leu Ala Glu Lys Gly Pro Gly Gln Gly Pro 405 410 415 Gly GlyAsp Gly His Gln Glu Ser Leu Pro Pro Pro Glu Phe Ser Lys 420 425 430 AspSer Gly Phe Leu Glu Glu Leu Pro Glu Asp Asn Leu Ser Ser Trp 435 440 445Ala Thr Trp Gly Thr Leu Pro Pro Glu Pro Asn Leu Val Pro Gly Gly 450 455460 Pro Pro Val Ser Leu Gln Thr Leu Thr Phe Cys Trp Glu Ser Ser Pro 465470 475 480 Glu Glu Glu Glu Glu Ala Arg Glu Ser Glu Ile Glu Asp Ser AspAla 485 490 495 Gly Ser Trp Gly Ala Glu Ser Thr Gln Arg Thr Glu Asp ArgGly Arg 500 505 510 Thr Leu Gly His Tyr Met Ala Arg 515 520 5 520 PRTHomo sapiens 5 Met Ala Gly Pro Glu Arg Trp Gly Pro Leu Leu Leu Cys LeuLeu Gln 1 5 10 15 Ala Ala Pro Gly Arg Pro Arg Leu Ala Pro Pro Gln AsnVal Thr Leu 20 25 30 Leu Ser Gln Asn Phe Ser Val Tyr Ile Thr Trp Leu ProGly Leu Gly 35 40 45 Asn Pro Gln Asp Val Thr Tyr Phe Val Ala Tyr Gln SerSer Pro Thr 50 55 60 Arg Arg Arg Trp Arg Glu Val Glu Glu Cys Ala Gly ThrLys Glu Leu 65 70 75 80 Leu Cys Ser Met Met Cys Leu Lys Lys Gln Asp LeuTyr Asn Lys Phe 85 90 95 Lys Gly Arg Val Arg Thr Val Ser Pro Ser Ser LysSer Pro Trp Val 100 105 110 Glu Ser Glu Tyr Leu Asp Tyr Leu Phe Glu ValGlu Pro Ala Pro Pro 115 120 125 Val Leu Val Leu Thr Gln Thr Glu Glu IleLeu Ser Ala Asn Ala Thr 130 135 140 Tyr Gln Leu Pro Pro Cys Met Pro ProLeu Asp Leu Lys Tyr Glu Val 145 150 155 160 Ala Phe Trp Lys Glu Gly AlaGly Asn Lys Thr Leu Phe Pro Val Thr 165 170 175 Pro His Gly Gln Pro ValGln Ile Thr Leu Gln Pro Ala Ala Ser Glu 180 185 190 His His Cys Leu SerAla Arg Thr Ile Tyr Thr Phe Ser Val Pro Lys 195 200 205 Tyr Ser Lys PheSer Lys Pro Thr Cys Phe Leu Leu Glu Val Pro Glu 210 215 220 Ala Asn TrpAla Phe Leu Val Leu Pro Ser Leu Leu Ile Leu Leu Leu 225 230 235 240 ValIle Ala Ala Gly Gly Val Ile Trp Lys Thr Leu Met Gly Asn Pro 245 250 255Trp Phe Gln Arg Ala Lys Met Pro Arg Ala Leu Asp Phe Ser Gly His 260 265270 Thr His Pro Val Ala Thr Phe Gln Pro Ser Arg Pro Glu Ser Val Asn 275280 285 Asp Leu Phe Leu Cys Pro Gln Lys Glu Leu Thr Arg Gly Val Arg Pro290 295 300 Thr Pro Arg Val Arg Ala Pro Ala Thr Gln Gln Thr Arg Trp LysLys 305 310 315 320 Asp Leu Ala Glu Asp Glu Glu Glu Glu Asp Glu Glu AspThr Glu Asp 325 330 335 Gly Val Ser Phe Gln Pro Tyr Ile Glu Pro Pro SerPhe Leu Gly Gln 340 345 350 Glu His Gln Ala Pro Gly His Ser Glu Ala GlyGly Val Asp Ser Gly 355 360 365 Arg Pro Arg Ala Pro Leu Val Pro Ser GluGly Ser Ser Ala Trp Asp 370 375 380 Ser Ser Asp Arg Ser Trp Ala Ser ThrVal Asp Ser Ser Trp Asp Arg 385 390 395 400 Ala Gly Ser Ser Gly Tyr LeuAla Glu Lys Gly Pro Gly Gln Gly Pro 405 410 415 Gly Gly Asp Gly His GlnGlu Ser Leu Pro Pro Pro Glu Phe Ser Lys 420 425 430 Asp Ser Gly Phe LeuGlu Glu Leu Pro Glu Asp Asn Leu Ser Ser Trp 435 440 445 Ala Thr Trp GlyThr Leu Pro Pro Glu Pro Asn Leu Val Pro Gly Gly 450 455 460 Pro Pro ValSer Leu Gln Thr Leu Thr Phe Cys Trp Glu Ser Ser Pro 465 470 475 480 GluGlu Glu Glu Glu Ala Arg Glu Ser Glu Ile Glu Asp Ser Asp Ala 485 490 495Gly Ser Trp Gly Ala Glu Ser Thr Gln Arg Thr Glu Asp Arg Gly Arg 500 505510 Thr Leu Gly His Tyr Met Ala Arg 515 520 6 520 PRT Homo sapiens 6 MetAla Gly Pro Glu Arg Trp Gly Pro Leu Leu Leu Cys Leu Leu Gln 1 5 10 15Ala Ala Pro Gly Arg Pro Arg Leu Ala Pro Pro Gln Asn Val Thr Leu 20 25 30Leu Ser Gln Asn Phe Ser Val Tyr Leu Thr Trp Leu Pro Gly Leu Gly 35 40 45Thr Pro Gln Asp Val Thr Tyr Phe Val Ala Tyr Gln Ser Ser Pro Thr 50 55 60Arg Arg Arg Trp Arg Glu Val Glu Glu Cys Ala Gly Thr Lys Glu Leu 65 70 7580 Leu Cys Ser Met Met Cys Leu Lys Lys Gln Asp Leu Tyr Asn Lys Phe 85 9095 Lys Gly Arg Val Arg Thr Val Ser Pro Ser Ser Lys Ser Pro Trp Val 100105 110 Glu Ser Glu Tyr Leu Asp Tyr Leu Phe Glu Val Glu Pro Ala Pro Pro115 120 125 Val Leu Val Leu Thr Gln Thr Glu Glu Ile Leu Ser Ala Asn AlaThr 130 135 140 Tyr Gln Leu Pro Pro Cys Met Pro Pro Leu Asp Leu Lys TyrGlu Val 145 150 155 160 Ala Phe Trp Lys Glu Gly Ala Gly Asn Lys Thr LeuPhe Pro Val Thr 165 170 175 Pro His Gly Gln Pro Val Gln Ile Thr Leu GlnPro Ala Ala Ser Glu 180 185 190 His His Cys Leu Ser Ala Arg Thr Ile TyrThr Phe Ser Val Pro Lys 195 200 205 Tyr Ser Lys Phe Ser Lys Pro Thr CysPhe Leu Leu Glu Val Pro Glu 210 215 220 Ala Asn Trp Ala Phe Leu Val LeuPro Ser Leu Leu Ile Leu Leu Leu 225 230 235 240 Val Ile Ala Ala Gly GlyVal Ile Trp Lys Thr Leu Met Gly Asn Pro 245 250 255 Trp Phe Gln Arg AlaLys Met Pro Arg Ala Leu Asp Phe Ser Gly His 260 265 270 Thr His Pro ValAla Thr Phe Gln Pro Ser Arg Pro Glu Ser Val Asn 275 280 285 Asp Leu PheLeu Cys Pro Gln Lys Glu Leu Thr Arg Gly Val Arg Pro 290 295 300 Thr ProArg Val Arg Ala Pro Ala Thr Gln Gln Thr Arg Trp Lys Lys 305 310 315 320Asp Leu Ala Glu Asp Glu Glu Glu Glu Asp Glu Glu Asp Thr Glu Asp 325 330335 Gly Val Ser Phe Gln Pro Tyr Ile Glu Pro Pro Ser Phe Leu Gly Gln 340345 350 Glu His Gln Ala Pro Gly His Ser Glu Ala Gly Gly Val Asp Ser Gly355 360 365 Arg Pro Arg Ala Pro Leu Val Pro Ser Glu Gly Ser Ser Ala TrpAsp 370 375 380 Ser Ser Asp Arg Ser Trp Ala Ser Thr Val Asp Ser Ser TrpAsp Arg 385 390 395 400 Ala Gly Ser Ser Gly Tyr Leu Ala Glu Lys Gly ProGly Gln Gly Pro 405 410 415 Gly Gly Asp Gly His Gln Glu Ser Leu Pro ProPro Glu Phe Ser Lys 420 425 430 Asp Ser Gly Phe Leu Glu Glu Leu Pro GluAsp Asn Leu Ser Ser Trp 435 440 445 Ala Thr Trp Gly Thr Leu Pro Pro GluPro Asn Leu Val Pro Gly Gly 450 455 460 Pro Pro Val Ser Leu Gln Thr LeuThr Phe Cys Trp Glu Ser Ser Pro 465 470 475 480 Glu Glu Glu Glu Glu AlaArg Glu Ser Glu Ile Glu Asp Ser Asp Ala 485 490 495 Gly Ser Trp Gly AlaGlu Ser Thr Gln Arg Thr Glu Asp Arg Gly Arg 500 505 510 Thr Leu Gly HisTyr Met Ala Arg 515 520 7 520 PRT Homo sapiens 7 Met Ala Gly Pro Glu ArgTrp Gly Pro Leu Leu Leu Cys Leu Leu Gln 1 5 10 15 Ala Ala Pro Gly ArgPro Arg Leu Ala Pro Pro Gln Asn Val Thr Leu 20 25 30 Leu Ser Gln Asn PheSer Val Tyr Leu Thr Trp Leu Pro Gly Leu Gly 35 40 45 Asn Pro Gln Asp ValThr Tyr Phe Val Ala Tyr Gln Ser Ser Pro Thr 50 55 60 Lys Arg Arg Trp ArgGlu Val Glu Glu Cys Ala Gly Thr Lys Glu Leu 65 70 75 80 Leu Cys Ser MetMet Cys Leu Lys Lys Gln Asp Leu Tyr Asn Lys Phe 85 90 95 Lys Gly Arg ValArg Thr Val Ser Pro Ser Ser Lys Ser Pro Trp Val 100 105 110 Glu Ser GluTyr Leu Asp Tyr Leu Phe Glu Val Glu Pro Ala Pro Pro 115 120 125 Val LeuVal Leu Thr Gln Thr Glu Glu Ile Leu Ser Ala Asn Ala Thr 130 135 140 TyrGln Leu Pro Pro Cys Met Pro Pro Leu Asp Leu Lys Tyr Glu Val 145 150 155160 Ala Phe Trp Lys Glu Gly Ala Gly Asn Lys Thr Leu Phe Pro Val Thr 165170 175 Pro His Gly Gln Pro Val Gln Ile Thr Leu Gln Pro Ala Ala Ser Glu180 185 190 His His Cys Leu Ser Ala Arg Thr Ile Tyr Thr Phe Ser Val ProLys 195 200 205 Tyr Ser Lys Phe Ser Lys Pro Thr Cys Phe Leu Leu Glu ValPro Glu 210 215 220 Ala Asn Trp Ala Phe Leu Val Leu Pro Ser Leu Leu IleLeu Leu Leu 225 230 235 240 Val Ile Ala Ala Gly Gly Val Ile Trp Lys ThrLeu Met Gly Asn Pro 245 250 255 Trp Phe Gln Arg Ala Lys Met Pro Arg AlaLeu Asp Phe Ser Gly His 260 265 270 Thr His Pro Val Ala Thr Phe Gln ProSer Arg Pro Glu Ser Val Asn 275 280 285 Asp Leu Phe Leu Cys Pro Gln LysGlu Leu Thr Arg Gly Val Arg Pro 290 295 300 Thr Pro Arg Val Arg Ala ProAla Thr Gln Gln Thr Arg Trp Lys Lys 305 310 315 320 Asp Leu Ala Glu AspGlu Glu Glu Glu Asp Glu Glu Asp Thr Glu Asp 325 330 335 Gly Val Ser PheGln Pro Tyr Ile Glu Pro Pro Ser Phe Leu Gly Gln 340 345 350 Glu His GlnAla Pro Gly His Ser Glu Ala Gly Gly Val Asp Ser Gly 355 360 365 Arg ProArg Ala Pro Leu Val Pro Ser Glu Gly Ser Ser Ala Trp Asp 370 375 380 SerSer Asp Arg Ser Trp Ala Ser Thr Val Asp Ser Ser Trp Asp Arg 385 390 395400 Ala Gly Ser Ser Gly Tyr Leu Ala Glu Lys Gly Pro Gly Gln Gly Pro 405410 415 Gly Gly Asp Gly His Gln Glu Ser Leu Pro Pro Pro Glu Phe Ser Lys420 425 430 Asp Ser Gly Phe Leu Glu Glu Leu Pro Glu Asp Asn Leu Ser SerTrp 435 440 445 Ala Thr Trp Gly Thr Leu Pro Pro Glu Pro Asn Leu Val ProGly Gly 450 455 460 Pro Pro Val Ser Leu Gln Thr Leu Thr Phe Cys Trp GluSer Ser Pro 465 470 475 480 Glu Glu Glu Glu Glu Ala Arg Glu Ser Glu IleGlu Asp Ser Asp Ala 485 490 495 Gly Ser Trp Gly Ala Glu Ser Thr Gln ArgThr Glu Asp Arg Gly Arg 500 505 510 Thr Leu Gly His Tyr Met Ala Arg 515520 8 520 PRT Homo sapiens 8 Met Ala Gly Pro Glu Arg Trp Gly Pro Leu LeuLeu Cys Leu Leu Gln 1 5 10 15 Ala Ala Pro Gly Arg Pro Arg Leu Ala ProPro Gln Asn Val Thr Leu 20 25 30 Leu Ser Gln Asn Phe Ser Val Tyr Leu ThrTrp Leu Pro Gly Leu Gly 35 40 45 Asn Pro Gln Asp Val Thr Tyr Phe Val AlaTyr Gln Ser Ser Pro Thr 50 55 60 Arg Arg Arg Trp Arg Glu Val Glu Glu CysAla Gly Thr Arg Glu Leu 65 70 75 80 Leu Cys Ser Met Met Cys Leu Lys LysGln Asp Leu Tyr Asn Lys Phe 85 90 95 Lys Gly Arg Val Arg Thr Val Ser ProSer Ser Lys Ser Pro Trp Val 100 105 110 Glu Ser Glu Tyr Leu Asp Tyr LeuPhe Glu Val Glu Pro Ala Pro Pro 115 120 125 Val Leu Val Leu Thr Gln ThrGlu Glu Ile Leu Ser Ala Asn Ala Thr 130 135 140 Tyr Gln Leu Pro Pro CysMet Pro Pro Leu Asp Leu Lys Tyr Glu Val 145 150 155 160 Ala Phe Trp LysGlu Gly Ala Gly Asn Lys Thr Leu Phe Pro Val Thr 165 170 175 Pro His GlyGln Pro Val Gln Ile Thr Leu Gln Pro Ala Ala Ser Glu 180 185 190 His HisCys Leu Ser Ala Arg Thr Ile Tyr Thr Phe Ser Val Pro Lys 195 200 205 TyrSer Lys Phe Ser Lys Pro Thr Cys Phe Leu Leu Glu Val Pro Glu 210 215 220Ala Asn Trp Ala Phe Leu Val Leu Pro Ser Leu Leu Ile Leu Leu Leu 225 230235 240 Val Ile Ala Ala Gly Gly Val Ile Trp Lys Thr Leu Met Gly Asn Pro245 250 255 Trp Phe Gln Arg Ala Lys Met Pro Arg Ala Leu Asp Phe Ser GlyHis 260 265 270 Thr His Pro Val Ala Thr Phe Gln Pro Ser Arg Pro Glu SerVal Asn 275 280 285 Asp Leu Phe Leu Cys Pro Gln Lys Glu Leu Thr Arg GlyVal Arg Pro 290 295 300 Thr Pro Arg Val Arg Ala Pro Ala Thr Gln Gln ThrArg Trp Lys Lys 305 310 315 320 Asp Leu Ala Glu Asp Glu Glu Glu Glu AspGlu Glu Asp Thr Glu Asp 325 330 335 Gly Val Ser Phe Gln Pro Tyr Ile GluPro Pro Ser Phe Leu Gly Gln 340 345 350 Glu His Gln Ala Pro Gly His SerGlu Ala Gly Gly Val Asp Ser Gly 355 360 365 Arg Pro Arg Ala Pro Leu ValPro Ser Glu Gly Ser Ser Ala Trp Asp 370 375 380 Ser Ser Asp Arg Ser TrpAla Ser Thr Val Asp Ser Ser Trp Asp Arg 385 390 395 400 Ala Gly Ser SerGly Tyr Leu Ala Glu Lys Gly Pro Gly Gln Gly Pro 405 410 415 Gly Gly AspGly His Gln Glu Ser Leu Pro Pro Pro Glu Phe Ser Lys 420 425 430 Asp SerGly Phe Leu Glu Glu Leu Pro Glu Asp Asn Leu Ser Ser Trp 435 440 445 AlaThr Trp Gly Thr Leu Pro Pro Glu Pro Asn Leu Val Pro Gly Gly 450 455 460Pro Pro Val Ser Leu Gln Thr Leu Thr Phe Cys Trp Glu Ser Ser Pro 465 470475 480 Glu Glu Glu Glu Glu Ala Arg Glu Ser Glu Ile Glu Asp Ser Asp Ala485 490 495 Gly Ser Trp Gly Ala Glu Ser Thr Gln Arg Thr Glu Asp Arg GlyArg 500 505 510 Thr Leu Gly His Tyr Met Ala Arg 515 520 9 520 PRT Homosapiens 9 Met Ala Gly Pro Glu Arg Trp Gly Pro Leu Leu Leu Cys Leu LeuGln 1 5 10 15 Ala Ala Pro Gly Arg Pro Arg Leu Ala Pro Pro Gln Asn ValThr Leu 20 25 30 Leu Ser Gln Asn Phe Ser Val Tyr Leu Thr Trp Leu Pro GlyLeu Gly 35 40 45 Asn Pro Gln Asp Val Thr Tyr Phe Val Ala Tyr Gln Ser SerPro Thr 50 55 60 Arg Arg Arg Trp Arg Glu Val Glu Glu Cys Ala Gly Thr LysGlu Leu 65 70 75 80 Leu Cys Ser Met Met Cys Leu Lys Lys Asn Asp Leu TyrAsn Lys Phe 85 90 95 Lys Gly Arg Val Arg Thr Val Ser Pro Ser Ser Lys SerPro Trp Val 100 105 110 Glu Ser Glu Tyr Leu Asp Tyr Leu Phe Glu Val GluPro Ala Pro Pro 115 120 125 Val Leu Val Leu Thr Gln Thr Glu Glu Ile LeuSer Ala Asn Ala Thr 130 135 140 Tyr Gln Leu Pro Pro Cys Met Pro Pro LeuAsp Leu Lys Tyr Glu Val 145 150 155 160 Ala Phe Trp Lys Glu Gly Ala GlyAsn Lys Thr Leu Phe Pro Val Thr 165 170 175 Pro His Gly Gln Pro Val GlnIle Thr Leu Gln Pro Ala Ala Ser Glu 180 185 190 His His Cys Leu Ser AlaArg Thr Ile Tyr Thr Phe Ser Val Pro Lys 195 200 205 Tyr Ser Lys Phe SerLys Pro Thr Cys Phe Leu Leu Glu Val Pro Glu 210 215 220 Ala Asn Trp AlaPhe Leu Val Leu Pro Ser Leu Leu Ile Leu Leu Leu 225 230 235 240 Val IleAla Ala Gly Gly Val Ile Trp Lys Thr Leu Met Gly Asn Pro 245 250 255 TrpPhe Gln Arg Ala Lys Met Pro Arg Ala Leu Asp Phe Ser Gly His 260 265 270Thr His Pro Val Ala Thr Phe Gln Pro Ser Arg Pro Glu Ser Val Asn 275 280285 Asp Leu Phe Leu Cys Pro Gln Lys Glu Leu Thr Arg Gly Val Arg Pro 290295 300 Thr Pro Arg Val Arg Ala Pro Ala Thr Gln Gln Thr Arg Trp Lys Lys305 310 315 320 Asp Leu Ala Glu Asp Glu Glu Glu Glu Asp Glu Glu Asp ThrGlu Asp 325 330 335 Gly Val Ser Phe Gln Pro Tyr Ile Glu Pro Pro Ser PheLeu Gly Gln 340 345 350 Glu His Gln Ala Pro Gly His Ser Glu Ala Gly GlyVal Asp Ser Gly 355 360 365 Arg Pro Arg Ala Pro Leu Val Pro Ser Glu GlySer Ser Ala Trp Asp 370 375 380 Ser Ser Asp Arg Ser Trp Ala Ser Thr ValAsp Ser Ser Trp Asp Arg 385 390 395 400 Ala Gly Ser Ser Gly Tyr Leu AlaGlu Lys Gly Pro Gly Gln Gly Pro 405 410 415 Gly Gly Asp Gly His Gln GluSer Leu Pro Pro Pro Glu Phe Ser Lys 420 425 430 Asp Ser Gly Phe Leu GluGlu Leu Pro Glu Asp Asn Leu Ser Ser Trp 435 440 445 Ala Thr Trp Gly ThrLeu Pro Pro Glu Pro Asn Leu Val Pro Gly Gly 450 455 460 Pro Pro Val SerLeu Gln Thr Leu Thr Phe Cys Trp Glu Ser Ser Pro 465 470 475 480 Glu GluGlu Glu Glu Ala Arg Glu Ser Glu Ile Glu Asp Ser Asp Ala 485 490 495 GlySer Trp Gly Ala Glu Ser Thr Gln Arg Thr Glu Asp Arg Gly Arg 500 505 510Thr Leu Gly His Tyr Met Ala Arg 515 520 10 520 PRT Homo sapiens 10 MetAla Gly Pro Glu Arg Trp Gly Pro Leu Leu Leu Cys Leu Leu Gln 1 5 10 15Ala Ala Pro Gly Arg Pro Arg Leu Ala Pro Pro Gln Asn Val Thr Leu 20 25 30Leu Ser Gln Asn Phe Ser Val Tyr Leu Thr Trp Leu Pro Gly Leu Gly 35 40 45Asn Pro Gln Asp Val Thr Tyr Phe Val Ala Tyr Gln Ser Ser Pro Thr 50 55 60Arg Arg Arg Trp Arg Glu Val Glu Glu Cys Ala Gly Thr Lys Glu Leu 65 70 7580 Leu Cys Ser Met Met Cys Leu Lys Lys Gln Asp Leu Tyr Asn Lys Phe 85 9095 Lys Gly Lys Val Arg Thr Val Ser Pro Ser Ser Lys Ser Pro Trp Val 100105 110 Glu Ser Glu Tyr Leu Asp Tyr Leu Phe Glu Val Glu Pro Ala Pro Pro115 120 125 Val Leu Val Leu Thr Gln Thr Glu Glu Ile Leu Ser Ala Asn AlaThr 130 135 140 Tyr Gln Leu Pro Pro Cys Met Pro Pro Leu Asp Leu Lys TyrGlu Val 145 150 155 160 Ala Phe Trp Lys Glu Gly Ala Gly Asn Lys Thr LeuPhe Pro Val Thr 165 170 175 Pro His Gly Gln Pro Val Gln Ile Thr Leu GlnPro Ala Ala Ser Glu 180 185 190 His His Cys Leu Ser Ala Arg Thr Ile TyrThr Phe Ser Val Pro Lys 195 200 205 Tyr Ser Lys Phe Ser Lys Pro Thr CysPhe Leu Leu Glu Val Pro Glu 210 215 220 Ala Asn Trp Ala Phe Leu Val LeuPro Ser Leu Leu Ile Leu Leu Leu 225 230 235 240 Val Ile Ala Ala Gly GlyVal Ile Trp Lys Thr Leu Met Gly Asn Pro 245 250 255 Trp Phe Gln Arg AlaLys Met Pro Arg Ala Leu Asp Phe Ser Gly His 260 265 270 Thr His Pro ValAla Thr Phe Gln Pro Ser Arg Pro Glu Ser Val Asn 275 280 285 Asp Leu PheLeu Cys Pro Gln Lys Glu Leu Thr Arg Gly Val Arg Pro 290 295 300 Thr ProArg Val Arg Ala Pro Ala Thr Gln Gln Thr Arg Trp Lys Lys 305 310 315 320Asp Leu Ala Glu Asp Glu Glu Glu Glu Asp Glu Glu Asp Thr Glu Asp 325 330335 Gly Val Ser Phe Gln Pro Tyr Ile Glu Pro Pro Ser Phe Leu Gly Gln 340345 350 Glu His Gln Ala Pro Gly His Ser Glu Ala Gly Gly Val Asp Ser Gly355 360 365 Arg Pro Arg Ala Pro Leu Val Pro Ser Glu Gly Ser Ser Ala TrpAsp 370 375 380 Ser Ser Asp Arg Ser Trp Ala Ser Thr Val Asp Ser Ser TrpAsp Arg 385 390 395 400 Ala Gly Ser Ser Gly Tyr Leu Ala Glu Lys Gly ProGly Gln Gly Pro 405 410 415 Gly Gly Asp Gly His Gln Glu Ser Leu Pro ProPro Glu Phe Ser Lys 420 425 430 Asp Ser Gly Phe Leu Glu Glu Leu Pro GluAsp Asn Leu Ser Ser Trp 435 440 445 Ala Thr Trp Gly Thr Leu Pro Pro GluPro Asn Leu Val Pro Gly Gly 450 455 460 Pro Pro Val Ser Leu Gln Thr LeuThr Phe Cys Trp Glu Ser Ser Pro 465 470 475 480 Glu Glu Glu Glu Glu AlaArg Glu Ser Glu Ile Glu Asp Ser Asp Ala 485 490 495 Gly Ser Trp Gly AlaGlu Ser Thr Gln Arg Thr Glu Asp Arg Gly Arg 500 505 510 Thr Leu Gly HisTyr Met Ala Arg 515 520 11 520 PRT Homo sapiens 11 Met Ala Gly Pro GluArg Trp Gly Pro Leu Leu Leu Cys Leu Leu Gln 1 5 10 15 Ala Ala Pro GlyArg Pro Arg Leu Ala Pro Pro Gln Asn Val Thr Leu 20 25 30 Leu Ser Gln AsnPhe Ser Val Tyr Leu Thr Trp Leu Pro Gly Leu Gly 35 40 45 Asn Pro Gln AspVal Thr Tyr Phe Val Ala Tyr Gln Ser Ser Pro Thr 50 55 60 Arg Arg Arg TrpArg Glu Val Glu Glu Cys Ala Gly Thr Lys Glu Leu 65 70 75 80 Leu Cys SerMet Met Cys Leu Lys Lys Gln Asp Leu Tyr Asn Lys Phe 85 90 95 Lys Gly ArgVal Arg Thr Val Ser Pro Ser Ser Lys Ser Pro Trp Leu 100 105 110 Glu SerGlu Tyr Leu Asp Tyr Leu Phe Glu Val Glu Pro Ala Pro Pro 115 120 125 ValLeu Val Leu Thr Gln Thr Glu Glu Ile Leu Ser Ala Asn Ala Thr 130 135 140Tyr Gln Leu Pro Pro Cys Met Pro Pro Leu Asp Leu Lys Tyr Glu Val 145 150155 160 Ala Phe Trp Lys Glu Gly Ala Gly Asn Lys Thr Leu Phe Pro Val Thr165 170 175 Pro His Gly Gln Pro Val Gln Ile Thr Leu Gln Pro Ala Ala SerGlu 180 185 190 His His Cys Leu Ser Ala Arg Thr Ile Tyr Thr Phe Ser ValPro Lys 195 200 205 Tyr Ser Lys Phe Ser Lys Pro Thr Cys Phe Leu Leu GluVal Pro Glu 210 215 220 Ala Asn Trp Ala Phe Leu Val Leu Pro Ser Leu LeuIle Leu Leu Leu 225 230 235 240 Val Ile Ala Ala Gly Gly Val Ile Trp LysThr Leu Met Gly Asn Pro 245 250 255 Trp Phe Gln Arg Ala Lys Met Pro ArgAla Leu Asp Phe Ser Gly His 260 265 270 Thr His Pro Val Ala Thr Phe GlnPro Ser Arg Pro Glu Ser Val Asn 275 280 285 Asp Leu Phe Leu Cys Pro GlnLys Glu Leu Thr Arg Gly Val Arg Pro 290 295 300 Thr Pro Arg Val Arg AlaPro Ala Thr Gln Gln Thr Arg Trp Lys Lys 305 310 315 320 Asp Leu Ala GluAsp Glu Glu Glu Glu Asp Glu Glu Asp Thr Glu Asp 325 330 335 Gly Val SerPhe Gln Pro Tyr Ile Glu Pro Pro Ser Phe Leu Gly Gln 340 345 350 Glu HisGln Ala Pro Gly His Ser Glu Ala Gly Gly Val Asp Ser Gly 355 360 365 ArgPro Arg Ala Pro Leu Val Pro Ser Glu Gly Ser Ser Ala Trp Asp 370 375 380Ser Ser Asp Arg Ser Trp Ala Ser Thr Val Asp Ser Ser Trp Asp Arg 385 390395 400 Ala Gly Ser Ser Gly Tyr Leu Ala Glu Lys Gly Pro Gly Gln Gly Pro405 410 415 Gly Gly Asp Gly His Gln Glu Ser Leu Pro Pro Pro Glu Phe SerLys 420 425 430 Asp Ser Gly Phe Leu Glu Glu Leu Pro Glu Asp Asn Leu SerSer Trp 435 440 445 Ala Thr Trp Gly Thr Leu Pro Pro Glu Pro Asn Leu ValPro Gly Gly 450 455 460 Pro Pro Val Ser Leu Gln Thr Leu Thr Phe Cys TrpGlu Ser Ser Pro 465 470 475 480 Glu Glu Glu Glu Glu Ala Arg Glu Ser GluIle Glu Asp Ser Asp Ala 485 490 495 Gly Ser Trp Gly Ala Glu Ser Thr GlnArg Thr Glu Asp Arg Gly Arg 500 505 510 Thr Leu Gly His Tyr Met Ala Arg515 520 12 520 PRT Homo sapiens 12 Met Ala Gly Pro Glu Arg Trp Gly ProLeu Leu Leu Cys Leu Leu Gln 1 5 10 15 Ala Ala Pro Gly Arg Pro Arg LeuAla Pro Pro Gln Asn Val Thr Leu 20 25 30 Leu Ser Gln Asn Phe Ser Val TyrLeu Thr Trp Leu Pro Gly Leu Gly 35 40 45 Asn Pro Gln Asp Val Thr Tyr PheVal Ala Tyr Gln Ser Ser Pro Thr 50 55 60 Arg Arg Arg Trp Arg Glu Val GluGlu Cys Ala Gly Thr Lys Glu Leu 65 70 75 80 Leu Cys Ser Met Met Cys LeuLys Lys Gln Asp Leu Tyr Asn Lys Phe 85 90 95 Lys Gly Arg Val Arg Thr ValSer Pro Ser Ser Lys Ser Pro Trp Val 100 105 110 Glu Ser Glu Phe Leu AspTyr Leu Phe Glu Val Glu Pro Ala Pro Pro 115 120 125 Val Leu Val Leu ThrGln Thr Glu Glu Ile Leu Ser Ala Asn Ala Thr 130 135 140 Tyr Gln Leu ProPro Cys Met Pro Pro Leu Asp Leu Lys Tyr Glu Val 145 150 155 160 Ala PheTrp Lys Glu Gly Ala Gly Asn Lys Thr Leu Phe Pro Val Thr 165 170 175 ProHis Gly Gln Pro Val Gln Ile Thr Leu Gln Pro Ala Ala Ser Glu 180 185 190His His Cys Leu Ser Ala Arg Thr Ile Tyr Thr Phe Ser Val Pro Lys 195 200205 Tyr Ser Lys Phe Ser Lys Pro Thr Cys Phe Leu Leu Glu Val Pro Glu 210215 220 Ala Asn Trp Ala Phe Leu Val Leu Pro Ser Leu Leu Ile Leu Leu Leu225 230 235 240 Val Ile Ala Ala Gly Gly Val Ile Trp Lys Thr Leu Met GlyAsn Pro 245 250 255 Trp Phe Gln Arg Ala Lys Met Pro Arg Ala Leu Asp PheSer Gly His 260 265 270 Thr His Pro Val Ala Thr Phe Gln Pro Ser Arg ProGlu Ser Val Asn 275 280 285 Asp Leu Phe Leu Cys Pro Gln Lys Glu Leu ThrArg Gly Val Arg Pro 290 295 300 Thr Pro Arg Val Arg Ala Pro Ala Thr GlnGln Thr Arg Trp Lys Lys 305 310 315 320 Asp Leu Ala Glu Asp Glu Glu GluGlu Asp Glu Glu Asp Thr Glu Asp 325 330 335 Gly Val Ser Phe Gln Pro TyrIle Glu Pro Pro Ser Phe Leu Gly Gln 340 345 350 Glu His Gln Ala Pro GlyHis Ser Glu Ala Gly Gly Val Asp Ser Gly 355 360 365 Arg Pro Arg Ala ProLeu Val Pro Ser Glu Gly Ser Ser Ala Trp Asp 370 375 380 Ser Ser Asp ArgSer Trp Ala Ser Thr Val Asp Ser Ser Trp Asp Arg 385 390 395 400 Ala GlySer Ser Gly Tyr Leu Ala Glu Lys Gly Pro Gly Gln Gly Pro 405 410 415 GlyGly Asp Gly His Gln Glu Ser Leu Pro Pro Pro Glu Phe Ser Lys 420 425 430Asp Ser Gly Phe Leu Glu Glu Leu Pro Glu Asp Asn Leu Ser Ser Trp 435 440445 Ala Thr Trp Gly Thr Leu Pro Pro Glu Pro Asn Leu Val Pro Gly Gly 450455 460 Pro Pro Val Ser Leu Gln Thr Leu Thr Phe Cys Trp Glu Ser Ser Pro465 470 475 480 Glu Glu Glu Glu Glu Ala Arg Glu Ser Glu Ile Glu Asp SerAsp Ala 485 490 495 Gly Ser Trp Gly Ala Glu Ser Thr Gln Arg Thr Glu AspArg Gly Arg 500 505 510 Thr Leu Gly His Tyr Met Ala Arg 515 520 13 520PRT Homo sapiens 13 Met Ala Gly Pro Glu Arg Trp Gly Pro Leu Leu Leu CysLeu Leu Gln 1 5 10 15 Ala Ala Pro Gly Arg Pro Arg Leu Ala Pro Pro GlnAsn Val Thr Leu 20 25 30 Leu Ser Gln Asn Phe Ser Val Tyr Leu Thr Trp LeuPro Gly Leu Gly 35 40 45 Asn Pro Gln Asp Val Thr Tyr Phe Val Ala Tyr GlnSer Ser Pro Thr 50 55 60 Arg Arg Arg Trp Arg Glu Val Glu Glu Cys Ala GlyThr Lys Glu Leu 65 70 75 80 Leu Cys Ser Met Met Cys Leu Lys Lys Gln AspLeu Tyr Asn Lys Phe 85 90 95 Lys Gly Arg Val Arg Thr Val Ser Pro Ser SerLys Ser Pro Trp Val 100 105 110 Glu Ser Glu Tyr Leu Asp Tyr Leu Phe GluVal Glu Pro Ala Pro Pro 115 120 125 Ile Leu Val Leu Thr Gln Thr Glu GluIle Leu Ser Ala Asn Ala Thr 130 135 140 Tyr Gln Leu Pro Pro Cys Met ProPro Leu Asp Leu Lys Tyr Glu Val 145 150 155 160 Ala Phe Trp Lys Glu GlyAla Gly Asn Lys Thr Leu Phe Pro Val Thr 165 170 175 Pro His Gly Gln ProVal Gln Ile Thr Leu Gln Pro Ala Ala Ser Glu 180 185 190 His His Cys LeuSer Ala Arg Thr Ile Tyr Thr Phe Ser Val Pro Lys 195 200 205 Tyr Ser LysPhe Ser Lys Pro Thr Cys Phe Leu Leu Glu Val Pro Glu 210 215 220 Ala AsnTrp Ala Phe Leu Val Leu Pro Ser Leu Leu Ile Leu Leu Leu 225 230 235 240Val Ile Ala Ala Gly Gly Val Ile Trp Lys Thr Leu Met Gly Asn Pro 245 250255 Trp Phe Gln Arg Ala Lys Met Pro Arg Ala Leu Asp Phe Ser Gly His 260265 270 Thr His Pro Val Ala Thr Phe Gln Pro Ser Arg Pro Glu Ser Val Asn275 280 285 Asp Leu Phe Leu Cys Pro Gln Lys Glu Leu Thr Arg Gly Val ArgPro 290 295 300 Thr Pro Arg Val Arg Ala Pro Ala Thr Gln Gln Thr Arg TrpLys Lys 305 310 315 320 Asp Leu Ala Glu Asp Glu Glu Glu Glu Asp Glu GluAsp Thr Glu Asp 325 330 335 Gly Val Ser Phe Gln Pro Tyr Ile Glu Pro ProSer Phe Leu Gly Gln 340 345 350 Glu His Gln Ala Pro Gly His Ser Glu AlaGly Gly Val Asp Ser Gly 355 360 365 Arg Pro Arg Ala Pro Leu Val Pro SerGlu Gly Ser Ser Ala Trp Asp 370 375 380 Ser Ser Asp Arg Ser Trp Ala SerThr Val Asp Ser Ser Trp Asp Arg 385 390 395 400 Ala Gly Ser Ser Gly TyrLeu Ala Glu Lys Gly Pro Gly Gln Gly Pro 405 410 415 Gly Gly Asp Gly HisGln Glu Ser Leu Pro Pro Pro Glu Phe Ser Lys 420 425 430 Asp Ser Gly PheLeu Glu Glu Leu Pro Glu Asp Asn Leu Ser Ser Trp 435 440 445 Ala Thr TrpGly Thr Leu Pro Pro Glu Pro Asn Leu Val Pro Gly Gly 450 455 460 Pro ProVal Ser Leu Gln Thr Leu Thr Phe Cys Trp Glu Ser Ser Pro 465 470 475 480Glu Glu Glu Glu Glu Ala Arg Glu Ser Glu Ile Glu Asp Ser Asp Ala 485 490495 Gly Ser Trp Gly Ala Glu Ser Thr Gln Arg Thr Glu Asp Arg Gly Arg 500505 510 Thr Leu Gly His Tyr Met Ala Arg 515 520 14 520 PRT Homo sapiens14 Met Ala Gly Pro Glu Arg Trp Gly Pro Leu Leu Leu Cys Leu Leu Gln 1 510 15 Ala Ala Pro Gly Arg Pro Arg Leu Ala Pro Pro Gln Asn Val Thr Leu 2025 30 Leu Ser Gln Asn Phe Ser Val Tyr Leu Thr Trp Leu Pro Gly Leu Gly 3540 45 Asn Pro Gln Asp Val Thr Tyr Phe Val Ala Tyr Gln Ser Ser Pro Thr 5055 60 Arg Arg Arg Trp Arg Glu Val Glu Glu Cys Ala Gly Thr Lys Glu Leu 6570 75 80 Leu Cys Ser Met Met Cys Leu Lys Lys Gln Asp Leu Tyr Asn Lys Phe85 90 95 Lys Gly Arg Val Arg Thr Val Ser Pro Ser Ser Lys Ser Pro Trp Val100 105 110 Glu Ser Glu Tyr Leu Asp Tyr Leu Phe Glu Val Glu Pro Ala ProPro 115 120 125 Val Leu Val Leu Thr Gln Thr Glu Glu Ile Leu Ser Ala AsnAla Asn 130 135 140 Tyr Gln Leu Pro Pro Cys Met Pro Pro Leu Asp Leu LysTyr Glu Val 145 150 155 160 Ala Phe Trp Lys Glu Gly Ala Gly Asn Lys ThrLeu Phe Pro Val Thr 165 170 175 Pro His Gly Gln Pro Val Gln Ile Thr LeuGln Pro Ala Ala Ser Glu 180 185 190 His His Cys Leu Ser Ala Arg Thr IleTyr Thr Phe Ser Val Pro Lys 195 200 205 Tyr Ser Lys Phe Ser Lys Pro ThrCys Phe Leu Leu Glu Val Pro Glu 210 215 220 Ala Asn Trp Ala Phe Leu ValLeu Pro Ser Leu Leu Ile Leu Leu Leu 225 230 235 240 Val Ile Ala Ala GlyGly Val Ile Trp Lys Thr Leu Met Gly Asn Pro 245 250 255 Trp Phe Gln ArgAla Lys Met Pro Arg Ala Leu Asp Phe Ser Gly His 260 265 270 Thr His ProVal Ala Thr Phe Gln Pro Ser Arg Pro Glu Ser Val Asn 275 280 285 Asp LeuPhe Leu Cys Pro Gln Lys Glu Leu Thr Arg Gly Val Arg Pro 290 295 300 ThrPro Arg Val Arg Ala Pro Ala Thr Gln Gln Thr Arg Trp Lys Lys 305 310 315320 Asp Leu Ala Glu Asp Glu Glu Glu Glu Asp Glu Glu Asp Thr Glu Asp 325330 335 Gly Val Ser Phe Gln Pro Tyr Ile Glu Pro Pro Ser Phe Leu Gly Gln340 345 350 Glu His Gln Ala Pro Gly His Ser Glu Ala Gly Gly Val Asp SerGly 355 360 365 Arg Pro Arg Ala Pro Leu Val Pro Ser Glu Gly Ser Ser AlaTrp Asp 370 375 380 Ser Ser Asp Arg Ser Trp Ala Ser Thr Val Asp Ser SerTrp Asp Arg 385 390 395 400 Ala Gly Ser Ser Gly Tyr Leu Ala Glu Lys GlyPro Gly Gln Gly Pro 405 410 415 Gly Gly Asp Gly His Gln Glu Ser Leu ProPro Pro Glu Phe Ser Lys 420 425 430 Asp Ser Gly Phe Leu Glu Glu Leu ProGlu Asp Asn Leu Ser Ser Trp 435 440 445 Ala Thr Trp Gly Thr Leu Pro ProGlu Pro Asn Leu Val Pro Gly Gly 450 455 460 Pro Pro Val Ser Leu Gln ThrLeu Thr Phe Cys Trp Glu Ser Ser Pro 465 470 475 480 Glu Glu Glu Glu GluAla Arg Glu Ser Glu Ile Glu Asp Ser Asp Ala 485 490 495 Gly Ser Trp GlyAla Glu Ser Thr Gln Arg Thr Glu Asp Arg Gly Arg 500 505 510 Thr Leu GlyHis Tyr Met Ala Arg 515 520 15 520 PRT Homo sapiens 15 Met Ala Gly ProGlu Arg Trp Gly Pro Leu Leu Leu Cys Leu Leu Gln 1 5 10 15 Ala Ala ProGly Arg Pro Arg Leu Ala Pro Pro Gln Asn Val Thr Leu 20 25 30 Leu Ser GlnAsn Phe Ser Val Tyr Leu Thr Trp Leu Pro Gly Leu Gly 35 40 45 Asn Pro GlnAsp Val Thr Tyr Phe Val Ala Tyr Gln Ser Ser Pro Thr 50 55 60 Arg Arg ArgTrp Arg Glu Val Glu Glu Cys Ala Gly Thr Lys Glu Leu 65 70 75 80 Leu CysSer Met Met Cys Leu Lys Lys Gln Asp Leu Tyr Asn Lys Phe 85 90 95 Lys GlyArg Val Arg Thr Val Ser Pro Ser Ser Lys Ser Pro Trp Val 100 105 110 GluSer Glu Tyr Leu Asp Tyr Leu Phe Glu Val Glu Pro Ala Pro Pro 115 120 125Val Leu Val Leu Thr Gln Thr Glu Glu Ile Leu Ser Ala Asn Ala Thr 130 135140 Tyr Gln Leu Pro Pro Cys Met Pro Pro Ala Asp Leu Lys Tyr Glu Val 145150 155 160 Ala Phe Trp Lys Glu Gly Ala Gly Asn Lys Thr Leu Phe Pro ValThr 165 170 175 Pro His Gly Gln Pro Val Gln Ile Thr Leu Gln Pro Ala AlaSer Glu 180 185 190 His His Cys Leu Ser Ala Arg Thr Ile Tyr Thr Phe SerVal Pro Lys 195 200 205 Tyr Ser Lys Phe Ser Lys Pro Thr Cys Phe Leu LeuGlu Val Pro Glu 210 215 220 Ala Asn Trp Ala Phe Leu Val Leu Pro Ser LeuLeu Ile Leu Leu Leu 225 230 235 240 Val Ile Ala Ala Gly Gly Val Ile TrpLys Thr Leu Met Gly Asn Pro 245 250 255 Trp Phe Gln Arg Ala Lys Met ProArg Ala Leu Asp Phe Ser Gly His 260 265 270 Thr His Pro Val Ala Thr PheGln Pro Ser Arg Pro Glu Ser Val Asn 275 280 285 Asp Leu Phe Leu Cys ProGln Lys Glu Leu Thr Arg Gly Val Arg Pro 290 295 300 Thr Pro Arg Val ArgAla Pro Ala Thr Gln Gln Thr Arg Trp Lys Lys 305 310 315 320 Asp Leu AlaGlu Asp Glu Glu Glu Glu Asp Glu Glu Asp Thr Glu Asp 325 330 335 Gly ValSer Phe Gln Pro Tyr Ile Glu Pro Pro Ser Phe Leu Gly Gln 340 345 350 GluHis Gln Ala Pro Gly His Ser Glu Ala Gly Gly Val Asp Ser Gly 355 360 365Arg Pro Arg Ala Pro Leu Val Pro Ser Glu Gly Ser Ser Ala Trp Asp 370 375380 Ser Ser Asp Arg Ser Trp Ala Ser Thr Val Asp Ser Ser Trp Asp Arg 385390 395 400 Ala Gly Ser Ser Gly Tyr Leu Ala Glu Lys Gly Pro Gly Gln GlyPro 405 410 415 Gly Gly Asp Gly His Gln Glu Ser Leu Pro Pro Pro Glu PheSer Lys 420 425 430 Asp Ser Gly Phe Leu Glu Glu Leu Pro Glu Asp Asn LeuSer Ser Trp 435 440 445 Ala Thr Trp Gly Thr Leu Pro Pro Glu Pro Asn LeuVal Pro Gly Gly 450 455 460 Pro Pro Val Ser Leu Gln Thr Leu Thr Phe CysTrp Glu Ser Ser Pro 465 470 475 480 Glu Glu Glu Glu Glu Ala Arg Glu SerGlu Ile Glu Asp Ser Asp Ala 485 490 495 Gly Ser Trp Gly Ala Glu Ser ThrGln Arg Thr Glu Asp Arg Gly Arg 500 505 510 Thr Leu Gly His Tyr Met AlaArg 515 520 16 520 PRT Homo sapiens 16 Met Ala Gly Pro Glu Arg Trp GlyPro Leu Leu Leu Cys Leu Leu Gln 1 5 10 15 Ala Ala Pro Gly Arg Pro ArgLeu Ala Pro Pro Gln Asn Val Thr Leu 20 25 30 Leu Ser Gln Asn Phe Ser ValTyr Leu Thr Trp Leu Pro Gly Leu Gly 35 40 45 Asn Pro Gln Asp Val Thr TyrPhe Val Ala Tyr Gln Ser Ser Pro Thr 50 55 60 Arg Arg Arg Trp Arg Glu ValGlu Glu Cys Ala Gly Thr Lys Glu Leu 65 70 75 80 Leu Cys Ser Met Met CysLeu Lys Lys Gln Asp Leu Tyr Asn Lys Phe 85 90 95 Lys Gly Arg Val Arg ThrVal Ser Pro Ser Ser Lys Ser Pro Trp Val 100 105 110 Glu Ser Glu Tyr LeuAsp Tyr Leu Phe Glu Val Glu Pro Ala Pro Pro 115 120 125 Val Leu Val LeuThr Gln Thr Glu Glu Ile Leu Ser Ala Asn Ala Thr 130 135 140 Tyr Gln LeuPro Pro Cys Met Pro Pro Leu Asp Leu Lys Tyr Glu Val 145 150 155 160 AlaPhe Trp Lys Glu Gly Ala Gly Asn Arg Thr Leu Phe Pro Val Thr 165 170 175Pro His Gly Gln Pro Val Gln Ile Thr Leu Gln Pro Ala Ala Ser Glu 180 185190 His His Cys Leu Ser Ala Arg Thr Ile Tyr Thr Phe Ser Val Pro Lys 195200 205 Tyr Ser Lys Phe Ser Lys Pro Thr Cys Phe Leu Leu Glu Val Pro Glu210 215 220 Ala Asn Trp Ala Phe Leu Val Leu Pro Ser Leu Leu Ile Leu LeuLeu 225 230 235 240 Val Ile Ala Ala Gly Gly Val Ile Trp Lys Thr Leu MetGly Asn Pro 245 250 255 Trp Phe Gln Arg Ala Lys Met Pro Arg Ala Leu AspPhe Ser Gly His 260 265 270 Thr His Pro Val Ala Thr Phe Gln Pro Ser ArgPro Glu Ser Val Asn 275 280 285 Asp Leu Phe Leu Cys Pro Gln Lys Glu LeuThr Arg Gly Val Arg Pro 290 295 300 Thr Pro Arg Val Arg Ala Pro Ala ThrGln Gln Thr Arg Trp Lys Lys 305 310 315 320 Asp Leu Ala Glu Asp Glu GluGlu Glu Asp Glu Glu Asp Thr Glu Asp 325 330 335 Gly Val Ser Phe Gln ProTyr Ile Glu Pro Pro Ser Phe Leu Gly Gln 340 345 350 Glu His Gln Ala ProGly His Ser Glu Ala Gly Gly Val Asp Ser Gly 355 360 365 Arg Pro Arg AlaPro Leu Val Pro Ser Glu Gly Ser Ser Ala Trp Asp 370 375 380 Ser Ser AspArg Ser Trp Ala Ser Thr Val Asp Ser Ser Trp Asp Arg 385 390 395 400 AlaGly Ser Ser Gly Tyr Leu Ala Glu Lys Gly Pro Gly Gln Gly Pro 405 410 415Gly Gly Asp Gly His Gln Glu Ser Leu Pro Pro Pro Glu Phe Ser Lys 420 425430 Asp Ser Gly Phe Leu Glu Glu Leu Pro Glu Asp Asn Leu Ser Ser Trp 435440 445 Ala Thr Trp Gly Thr Leu Pro Pro Glu Pro Asn Leu Val Pro Gly Gly450 455 460 Pro Pro Val Ser Leu Gln Thr Leu Thr Phe Cys Trp Glu Ser SerPro 465 470 475 480 Glu Glu Glu Glu Glu Ala Arg Glu Ser Glu Ile Glu AspSer Asp Ala 485 490 495 Gly Ser Trp Gly Ala Glu Ser Thr Gln Arg Thr GluAsp Arg Gly Arg 500 505 510 Thr Leu Gly His Tyr Met Ala Arg 515 520 17520 PRT Homo sapiens 17 Met Ala Gly Pro Glu Arg Trp Gly Pro Leu Leu LeuCys Leu Leu Gln 1 5 10 15 Ala Ala Pro Gly Arg Pro Arg Leu Ala Pro ProGln Asn Val Thr Leu 20 25 30 Leu Ser Gln Asn Phe Ser Val Tyr Leu Thr TrpLeu Pro Gly Leu Gly 35 40 45 Asn Pro Gln Asp Val Thr Tyr Phe Val Ala TyrGln Ser Ser Pro Thr 50 55 60 Arg Arg Arg Trp Arg Glu Val Glu Glu Cys AlaGly Thr Lys Glu Leu 65 70 75 80 Leu Cys Ser Met Met Cys Leu Lys Lys GlnAsp Leu Tyr Asn Lys Phe 85 90 95 Lys Gly Arg Val Arg Thr Val Ser Pro SerSer Lys Ser Pro Trp Val 100 105 110 Glu Ser Glu Tyr Leu Asp Tyr Leu PheGlu Val Glu Pro Ala Pro Pro 115 120 125 Val Leu Val Leu Thr Gln Thr GluGlu Ile Leu Ser Ala Asn Ala Thr 130 135 140 Tyr Gln Leu Pro Pro Cys MetPro Pro Leu Asp Leu Lys Tyr Glu Val 145 150 155 160 Ala Phe Trp Lys GluGly Ala Gly Asn Lys Thr Leu Phe Pro Leu Thr 165 170 175 Pro His Gly GlnPro Val Gln Ile Thr Leu Gln Pro Ala Ala Ser Glu 180 185 190 His His CysLeu Ser Ala Arg Thr Ile Tyr Thr Phe Ser Val Pro Lys 195 200 205 Tyr SerLys Phe Ser Lys Pro Thr Cys Phe Leu Leu Glu Val Pro Glu 210 215 220 AlaAsn Trp Ala Phe Leu Val Leu Pro Ser Leu Leu Ile Leu Leu Leu 225 230 235240 Val Ile Ala Ala Gly Gly Val Ile Trp Lys Thr Leu Met Gly Asn Pro 245250 255 Trp Phe Gln Arg Ala Lys Met Pro Arg Ala Leu Asp Phe Ser Gly His260 265 270 Thr His Pro Val Ala Thr Phe Gln Pro Ser Arg Pro Glu Ser ValAsn 275 280 285 Asp Leu Phe Leu Cys Pro Gln Lys Glu Leu Thr Arg Gly ValArg Pro 290 295 300 Thr Pro Arg Val Arg Ala Pro Ala Thr Gln Gln Thr ArgTrp Lys Lys 305 310 315 320 Asp Leu Ala Glu Asp Glu Glu Glu Glu Asp GluGlu Asp Thr Glu Asp 325 330 335 Gly Val Ser Phe Gln Pro Tyr Ile Glu ProPro Ser Phe Leu Gly Gln 340 345 350 Glu His Gln Ala Pro Gly His Ser GluAla Gly Gly Val Asp Ser Gly 355 360 365 Arg Pro Arg Ala Pro Leu Val ProSer Glu Gly Ser Ser Ala Trp Asp 370 375 380 Ser Ser Asp Arg Ser Trp AlaSer Thr Val Asp Ser Ser Trp Asp Arg 385 390 395 400 Ala Gly Ser Ser GlyTyr Leu Ala Glu Lys Gly Pro Gly Gln Gly Pro 405 410 415 Gly Gly Asp GlyHis Gln Glu Ser Leu Pro Pro Pro Glu Phe Ser Lys 420 425 430 Asp Ser GlyPhe Leu Glu Glu Leu Pro Glu Asp Asn Leu Ser Ser Trp 435 440 445 Ala ThrTrp Gly Thr Leu Pro Pro Glu Pro Asn Leu Val Pro Gly Gly 450 455 460 ProPro Val Ser Leu Gln Thr Leu Thr Phe Cys Trp Glu Ser Ser Pro 465 470 475480 Glu Glu Glu Glu Glu Ala Arg Glu Ser Glu Ile Glu Asp Ser Asp Ala 485490 495 Gly Ser Trp Gly Ala Glu Ser Thr Gln Arg Thr Glu Asp Arg Gly Arg500 505 510 Thr Leu Gly His Tyr Met Ala Arg 515 520 18 520 PRT Homosapiens 18 Met Ala Gly Pro Glu Arg Trp Gly Pro Leu Leu Leu Cys Leu LeuGln 1 5 10 15 Ala Ala Pro Gly Arg Pro Arg Leu Ala Pro Pro Gln Asn ValThr Leu 20 25 30 Leu Ser Gln Asn Phe Ser Val Tyr Leu Thr Trp Leu Pro GlyLeu Gly 35 40 45 Asn Pro Gln Asp Val Thr Tyr Phe Val Ala Tyr Gln Ser SerPro Thr 50 55 60 Arg Arg Arg Trp Arg Glu Val Glu Glu Cys Ala Gly Thr LysGlu Leu 65 70 75 80 Leu Cys Ser Met Met Cys Leu Lys Lys Gln Asp Leu TyrAsn Lys Phe 85 90 95 Lys Gly Arg Val Arg Thr Val Ser Pro Ser Ser Lys SerPro Trp Val 100 105 110 Glu Ser Glu Tyr Leu Asp Tyr Leu Phe Glu Val GluPro Ala Pro Pro 115 120 125 Val Leu Val Leu Thr Gln Thr Glu Glu Ile LeuSer Ala Asn Ala Thr 130 135 140 Tyr Gln Leu Pro Pro Cys Met Pro Pro LeuAsp Leu Lys Tyr Glu Val 145 150 155 160 Ala Phe Trp Lys Glu Gly Ala GlyAsn Lys Thr Leu Phe Pro Val Thr 165 170 175 Pro His Gly Gln Pro Val GlnIle Thr Leu Gln Pro Val Ala Ser Glu 180 185 190 His His Cys Leu Ser AlaArg Thr Ile Tyr Thr Phe Ser Val Pro Lys 195 200 205 Tyr Ser Lys Phe SerLys Pro Thr Cys Phe Leu Leu Glu Val Pro Glu 210 215 220 Ala Asn Trp AlaPhe Leu Val Leu Pro Ser Leu Leu Ile Leu Leu Leu 225 230 235 240 Val IleAla Ala Gly Gly Val Ile Trp Lys Thr Leu Met Gly Asn Pro 245 250 255 TrpPhe Gln Arg Ala Lys Met Pro Arg Ala Leu Asp Phe Ser Gly His 260 265 270Thr His Pro Val Ala Thr Phe Gln Pro Ser Arg Pro Glu Ser Val Asn 275 280285 Asp Leu Phe Leu Cys Pro Gln Lys Glu Leu Thr Arg Gly Val Arg Pro 290295 300 Thr Pro Arg Val Arg Ala Pro Ala Thr Gln Gln Thr Arg Trp Lys Lys305 310 315 320 Asp Leu Ala Glu Asp Glu Glu Glu Glu Asp Glu Glu Asp ThrGlu Asp 325 330 335 Gly Val Ser Phe Gln Pro Tyr Ile Glu Pro Pro Ser PheLeu Gly Gln 340 345 350 Glu His Gln Ala Pro Gly His Ser Glu Ala Gly GlyVal Asp Ser Gly 355 360 365 Arg Pro Arg Ala Pro Leu Val Pro Ser Glu GlySer Ser Ala Trp Asp 370 375 380 Ser Ser Asp Arg Ser Trp Ala Ser Thr ValAsp Ser Ser Trp Asp Arg 385 390 395 400 Ala Gly Ser Ser Gly Tyr Leu AlaGlu Lys Gly Pro Gly Gln Gly Pro 405 410 415 Gly Gly Asp Gly His Gln GluSer Leu Pro Pro Pro Glu Phe Ser Lys 420 425 430 Asp Ser Gly Phe Leu GluGlu Leu Pro Glu Asp Asn Leu Ser Ser Trp 435 440 445 Ala Thr Trp Gly ThrLeu Pro Pro Glu Pro Asn Leu Val Pro Gly Gly 450 455 460 Pro Pro Val SerLeu Gln Thr Leu Thr Phe Cys Trp Glu Ser Ser Pro 465 470 475 480 Glu GluGlu Glu Glu Ala Arg Glu Ser Glu Ile Glu Asp Ser Asp Ala 485 490 495 GlySer Trp Gly Ala Glu Ser Thr Gln Arg Thr Glu Asp Arg Gly Arg 500 505 510Thr Leu Gly His Tyr Met Ala Arg 515 520 19 520 PRT Homo sapiens 19 MetAla Gly Pro Glu Arg Trp Gly Pro Leu Leu Leu Cys Leu Leu Gln 1 5 10 15Ala Ala Pro Gly Arg Pro Arg Leu Ala Pro Pro Gln Asn Val Thr Leu 20 25 30Leu Ser Gln Asn Phe Ser Val Tyr Leu Thr Trp Leu Pro Gly Leu Gly 35 40 45Asn Pro Gln Asp Val Thr Tyr Phe Val Ala Tyr Gln Ser Ser Pro Thr 50 55 60Arg Arg Arg Trp Arg Glu Val Glu Glu Cys Ala Gly Thr Lys Glu Leu 65 70 7580 Leu Cys Ser Met Met Cys Leu Lys Lys Gln Asp Leu Tyr Asn Lys Phe 85 9095 Lys Gly Arg Val Arg Thr Val Ser Pro Ser Ser Lys Ser Pro Trp Val 100105 110 Glu Ser Glu Tyr Leu Asp Tyr Leu Phe Glu Val Glu Pro Ala Pro Pro115 120 125 Val Leu Val Leu Thr Gln Thr Glu Glu Ile Leu Ser Ala Asn AlaThr 130 135 140 Tyr Gln Leu Pro Pro Cys Met Pro Pro Leu Asp Leu Lys TyrGlu Val 145 150 155 160 Ala Phe Trp Lys Glu Gly Ala Gly Asn Lys Thr LeuPhe Pro Val Thr 165 170 175 Pro His Gly Gln Pro Val Gln Ile Thr Leu GlnPro Ala Ala Ser Glu 180 185 190 His His Cys Leu Ser Ala Lys Thr Ile TyrThr Phe Ser Val Pro Lys 195 200 205 Tyr Ser Lys Phe Ser Lys Pro Thr CysPhe Leu Leu Glu Val Pro Glu 210 215 220 Ala Asn Trp Ala Phe Leu Val LeuPro Ser Leu Leu Ile Leu Leu Leu 225 230 235 240 Val Ile Ala Ala Gly GlyVal Ile Trp Lys Thr Leu Met Gly Asn Pro 245 250 255 Trp Phe Gln Arg AlaLys Met Pro Arg Ala Leu Asp Phe Ser Gly His 260 265 270 Thr His Pro ValAla Thr Phe Gln Pro Ser Arg Pro Glu Ser Val Asn 275 280 285 Asp Leu PheLeu Cys Pro Gln Lys Glu Leu Thr Arg Gly Val Arg Pro 290 295 300 Thr ProArg Val Arg Ala Pro Ala Thr Gln Gln Thr Arg Trp Lys Lys 305 310 315 320Asp Leu Ala Glu Asp Glu Glu Glu Glu Asp Glu Glu Asp Thr Glu Asp 325 330335 Gly Val Ser Phe Gln Pro Tyr Ile Glu Pro Pro Ser Phe Leu Gly Gln 340345 350 Glu His Gln Ala Pro Gly His Ser Glu Ala Gly Gly Val Asp Ser Gly355 360 365 Arg Pro Arg Ala Pro Leu Val Pro Ser Glu Gly Ser Ser Ala TrpAsp 370 375 380 Ser Ser Asp Arg Ser Trp Ala Ser Thr Val Asp Ser Ser TrpAsp Arg 385 390 395 400 Ala Gly Ser Ser Gly Tyr Leu Ala Glu Lys Gly ProGly Gln Gly Pro 405 410 415 Gly Gly Asp Gly His Gln Glu Ser Leu Pro ProPro Glu Phe Ser Lys 420 425 430 Asp Ser Gly Phe Leu Glu Glu Leu Pro GluAsp Asn Leu Ser Ser Trp 435 440 445 Ala Thr Trp Gly Thr Leu Pro Pro GluPro Asn Leu Val Pro Gly Gly 450 455 460 Pro Pro Val Ser Leu Gln Thr LeuThr Phe Cys Trp Glu Ser Ser Pro 465 470 475 480 Glu Glu Glu Glu Glu AlaArg Glu Ser Glu Ile Glu Asp Ser Asp Ala 485 490 495 Gly Ser Trp Gly AlaGlu Ser Thr Gln Arg Thr Glu Asp Arg Gly Arg 500 505 510 Thr Leu Gly HisTyr Met Ala Arg 515 520 20 520 PRT Homo sapiens 20 Met Ala Gly Pro GluArg Trp Gly Pro Leu Leu Leu Cys Leu Leu Gln 1 5 10 15 Ala Ala Pro GlyArg Pro Arg Leu Ala Pro Pro Gln Asn Val Thr Leu 20 25 30 Leu Ser Gln AsnPhe Ser Val Tyr Leu Thr Trp Leu Pro Gly Leu Gly 35 40 45 Asn Pro Gln AspVal Thr Tyr Phe Val Ala Tyr Gln Ser Ser Pro Thr 50 55 60 Arg Arg Arg TrpArg Glu Val Glu Glu Cys Ala Gly Thr Lys Glu Leu 65 70 75 80 Leu Cys SerMet Met Cys Leu Lys Lys Gln Asp Leu Tyr Asn Lys Phe 85 90 95 Lys Gly ArgVal Arg Thr Val Ser Pro Ser Ser Lys Ser Pro Trp Val 100 105 110 Glu SerGlu Tyr Leu Asp Tyr Leu Phe Glu Val Glu Pro Ala Pro Pro 115 120 125 ValLeu Val Leu Thr Gln Thr Glu Glu Ile Leu Ser Ala Asn Ala Thr 130 135 140Tyr Gln Leu Pro Pro Cys Met Pro Pro Leu Asp Leu Lys Tyr Glu Val 145 150155 160 Ala Phe Trp Lys Glu Gly Ala Gly Asn Lys Thr Leu Phe Pro Val Thr165 170 175 Pro His Gly Gln Pro Val Gln Ile Thr Leu Gln Pro Ala Ala SerGlu 180 185 190 His His Cys Leu Ser Ala Arg Thr Ile Tyr Thr Phe Ser ValPro Lys 195 200 205 Tyr Ser Lys Trp Ser Lys Pro Thr Cys Phe Leu Leu GluVal Pro Glu 210 215 220 Ala Asn Trp Ala Phe Leu Val Leu Pro Ser Leu LeuIle Leu Leu Leu 225 230 235 240 Val Ile Ala Ala Gly Gly Val Ile Trp LysThr Leu Met Gly Asn Pro 245 250 255 Trp Phe Gln Arg Ala Lys Met Pro ArgAla Leu Asp Phe Ser Gly His 260 265 270 Thr His Pro Val Ala Thr Phe GlnPro Ser Arg Pro Glu Ser Val Asn 275 280 285 Asp Leu Phe Leu Cys Pro GlnLys Glu Leu Thr Arg Gly Val Arg Pro 290 295 300 Thr Pro Arg Val Arg AlaPro Ala Thr Gln Gln Thr Arg Trp Lys Lys 305 310 315 320 Asp Leu Ala GluAsp Glu Glu Glu Glu Asp Glu Glu Asp Thr Glu Asp 325 330 335 Gly Val SerPhe Gln Pro Tyr Ile Glu Pro Pro Ser Phe Leu Gly Gln 340 345 350 Glu HisGln Ala Pro Gly His Ser Glu Ala Gly Gly Val Asp Ser Gly 355 360 365 ArgPro Arg Ala Pro Leu Val Pro Ser Glu Gly Ser Ser Ala Trp Asp 370 375 380Ser Ser Asp Arg Ser Trp Ala Ser Thr Val Asp Ser Ser Trp Asp Arg 385 390395 400 Ala Gly Ser Ser Gly Tyr Leu Ala Glu Lys Gly Pro Gly Gln Gly Pro405 410 415 Gly Gly Asp Gly His Gln Glu Ser Leu Pro Pro Pro Glu Phe SerLys 420 425 430 Asp Ser Gly Phe Leu Glu Glu Leu Pro Glu Asp Asn Leu SerSer Trp 435 440 445 Ala Thr Trp Gly Thr Leu Pro Pro Glu Pro Asn Leu ValPro Gly Gly 450 455 460 Pro Pro Val Ser Leu Gln Thr Leu Thr Phe Cys TrpGlu Ser Ser Pro 465 470 475 480 Glu Glu Glu Glu Glu Ala Arg Glu Ser GluIle Glu Asp Ser Asp Ala 485 490 495 Gly Ser Trp Gly Ala Glu Ser Thr GlnArg Thr Glu Asp Arg Gly Arg 500 505 510 Thr Leu Gly His Tyr Met Ala Arg515 520 21 520 PRT Homo sapiens 21 Met Ala Gly Pro Glu Arg Trp Gly ProLeu Leu Leu Cys Leu Leu Gln 1 5 10 15 Ala Ala Pro Gly Arg Pro Arg LeuAla Pro Pro Gln Asn Val Thr Leu 20 25 30 Leu Ser Gln Asn Phe Ser Val TyrLeu Thr Trp Leu Pro Gly Leu Gly 35 40 45 Asn Pro Gln Asp Val Thr Tyr PheVal Ala Tyr Gln Ser Ser Pro Thr 50 55 60 Arg Arg Arg Trp Arg Glu Val GluGlu Cys Ala Gly Thr Lys Glu Leu 65 70 75 80 Leu Cys Ser Met Met Cys LeuLys Lys Gln Asp Leu Tyr Asn Lys Phe 85 90 95 Lys Gly Arg Val Arg Thr ValSer Pro Ser Ser Lys Ser Pro Trp Val 100 105 110 Glu Ser Glu Tyr Leu AspTyr Leu Phe Glu Val Glu Pro Ala Pro Pro 115 120 125 Val Leu Val Leu ThrGln Thr Glu Glu Ile Leu Ser Ala Asn Ala Thr 130 135 140 Tyr Gln Leu ProPro Cys Met Pro Pro Leu Asp Leu Lys Tyr Glu Val 145 150 155 160 Ala PheTrp Lys Glu Gly Ala Gly Asn Lys Thr Leu Phe Pro Val Thr 165 170 175 ProHis Gly Gln Pro Val Gln Ile Thr Leu Gln Pro Ala Ala Ser Glu 180 185 190His His Cys Leu Ser Ala Arg Thr Ile Tyr Thr Phe Ser Val Pro Lys 195 200205 Tyr Ser Lys Phe Ser Lys Pro Thr Cys Phe Leu Leu Glu Val Pro Glu 210215 220 Ala Asn Trp Ala Phe Leu Val Leu Pro Ser Leu Leu Ile Leu Leu Leu225 230 235 240 Val Ile Ala Ala Gly Gly Val Ile Trp Lys Thr Leu Met GlyAsn Pro 245 250 255 Trp Phe Gln Arg Ala Lys Met Pro Arg Ala Leu Asp PheSer Gly His 260 265 270 Thr His Pro Val Ala Thr Phe Gln Pro Ser Arg ProGlu Ser Val Asn 275 280 285 Asp Leu Phe Leu Cys Pro Gln Lys Glu Leu ThrArg Gly Val Arg Pro 290 295 300 Thr Pro Arg Val Arg Ala Pro Ala Thr GlnGln Thr Arg Trp Lys Lys 305 310 315 320 Asp Leu Ala Glu Asp Glu Glu GluGlu Asp Glu Glu Asp Thr Glu Asp 325 330 335 Gly Val Ser Phe Gln Pro TyrIle Glu Pro Pro Ser Phe Leu Gly Gln 340 345 350 Glu His Gln Ala Pro GlyHis Ser Glu Ala Gly Gly Val Asp Ser Gly 355 360 365 Arg Pro Arg Ala ProLeu Val Pro Ser Glu Gly Ser Ser Ala Trp Asp 370 375 380 Ser Ser Asp ArgSer Trp Ala Ser Thr Val Asp Ser Ser Trp Asp Arg 385 390 395 400 Ala GlySer Ser Gly Tyr Leu Ala Glu Lys Gly Pro Gly Gln Gly Pro 405 410 415 GlyGly Asp Gly His Gln Glu Ser Leu Pro Pro Pro Glu Phe Ser Lys 420 425 430Asp Ser Gly Phe Leu Glu Glu Leu Pro Glu Asp Asn Leu Ser Ser Trp 435 440445 Ala Thr Trp Gly Thr Leu Pro Pro Glu Pro Asn Leu Val Pro Gly Gly 450455 460 Pro Pro Val Ser Leu Gln Thr Leu Thr Phe Cys Trp Glu Ser Ser Pro465 470 475 480 Glu Glu Glu Glu Glu Ala Arg Glu Ser Glu Ile Glu Asp SerAsp Ala 485 490 495 Gly Ser Trp Gly Ala Glu Ser Thr Gln Arg Thr Glu AspArg Gly Arg 500 505 510 Thr Leu Gly His Tyr Met Ala Lys 515 520 22 34757DNA Homo sapiens 22 aggaaggaag gaaggaagga aggaaggaag gaaagaaagaaagaaagaaa gaaagaaaga 60 aagaaagaaa gaaagaaaga aagaaagaaa gaaagagaaaggaaggaagg aaggagaaaa 120 gaaagtcaac agtcaacatt tcagagatcc caagataccaacactgaccg tgcctgctgc 180 tcttccatcc tcctccaccc tgcgcctttg aggtggaattgcgtcctctg tgagcagggc 240 tttgttaaga gatcctaatt aaggccaggc acagtggctcatgcctgtaa tcccagcact 300 ttgggaggct gaggtcacct gaggtcagga gttcaagaccagcctgccca acatggtgaa 360 accccatctc tacaaaaatt agctgagcat gatggcaggtgcctgtaatc ccaactactt 420 gggaggctga agtgagaaaa tagcttgaac ccaggaggcggggttgcagt gagccaagat 480 cacactattg cattccagcc tgggcgacag agcttttgtctaaaaaaaaa aaaagaaaaa 540 aaatcctgat taagcagaag ccttgatgct agtcccagaagcatcctgaa atttccaaaa 600 gaaatttccc ccgcggttaa actcagagca acttttggacccaccaagct ctgtgaaaat 660 cattttctct tccaaaaact gatgggacca aagctgatcccagtttcaaa taattatcaa 720 aaaattggaa acgaaatatg atcagaaaag aagaaagttgaaaaagaaaa tcctcatcac 780 ccaaagacaa caaccattaa tattttggta attattattccaaatatctt tctatgcata 840 cagacagact gacacacaca cacacacaca cacacacacacacacacaca cttttttttt 900 ttttttgaaa ctgagtttca ctctgtcgcc caggctggagtgcagtggcg cgatctcggc 960 tcactgcaac ctccgcctcc tgggttcaag cgattctcctgcctcagcct ccctgatagc 1020 tgggattaca ggtgaatgcc accacgcccg gctgattttctgtattttta gtagagacgg 1080 ggtttcacca tgttggccag gcttgtctcc aactcctgacctcaggcgat ccacccgcct 1140 caccctccca aagtgctggg attacaggcg tgagccaccgcgcccggcta cacacacact 1200 tttttaatgg gcctatgttt tagcactcgc ttttctgtttctcagtgtgt tgcaaacacc 1260 tcggtgtcga tacacaccat tcggcaacgt cctcctaaagggccgcataa tattgcgcgt 1320 cgtggcgtgt gccttactgg gaagctactg ctgtccaggtgaacaccaca gccttcgggg 1380 tcagaaagac agctttcccc agaacaagca cctgaagctctggggcctgc cgctccccgg 1440 gagagaagta cgtggagaag ggcagcacgg atccgccgggatccccgggg gcattaaagg 1500 gaatcgcgtg tgtaaggcgc ggagctcagc atccggctcagaaacgcgct cggatcccgc 1560 caatggcatt gaggccgcgt agccaaaccg gccttgaactctccctaatc ctgccaaaat 1620 ggcccgtcct ggagcactgg actggccgtg ggttattgatcatcagccgg tttcttcccc 1680 tcccctgccc ttcccccgtg cacggattta ctgatttttttttccgggaa ttgagtaaaa 1740 caaaactaag tgcagatgaa gcagaggtac gggcgagtttcgagcgcggg gaccggcgcg 1800 ctcccccccc cccctccccc cgcggcgggg ctgtccccagggaccttctc agtgaatcct 1860 aggcggcagg gacgggcccg cggctctgcg ggccattggctgccgactgc gtcacctgcc 1920 cgcggtgggc taggagacgg gaggcgggag gcgggaggcggggacctggg tccgggcggg 1980 gacgccgcgg caggaaggcc atggcggggc ccgagcgctggggccccctg ctcctgtgcc 2040 tgctgcaggc cgctccaggt aagggcgcgg ggccgcgggagggaggggga agagggctcc 2100 ccgggccggg ccgcgcctac cctcggaccc ggagctcctgggacaggcac ggggtccgca 2160 gccacccgag ccgggtgcga atcggccctg cctacgcgcccccagtttgc ttcttcccag 2220 gactgaacag aaccgggtct ttgatattcc tctcccgcaggaaacgaatc cagtttccta 2280 atgcttccag cttcaggaga actggagaaa aaagacagcggcagtttgat actgcatatt 2340 ttttaataaa gtgcttttta atgtttccta aagaaagcactgatccctgc gtgaaaacca 2400 cacttgaccc taaagtgtgg acagcaggga aagtgggaccgattgatgtc ccttcccgtt 2460 cctgccaggc ctctggtggg acggagctct ggtcgcctgtgccctgcttt ctaacaagac 2520 ggctttcttt tggtggtggt tgttgttttg ttgttgttttgttgttgttg ttgttgttgt 2580 tgttttccca cctctactga tgagtaaggt gtcaggtacaaaattcctcg ccgtaggacc 2640 caaccaccaa acctcaccgc ccacgactcc aaccgaagcagggaagagaa ggtccagaaa 2700 tcgcccccag gatattttcc tagtcttgga ctcacagtttaaagagctgt aaaggtccct 2760 gggcataatc caatcatcat aaaagcctat atttattcagcaacttcttt gtgccaggca 2820 ccgcattatt ctggaagcct cacgacccag ccatcctaggaggtagatat tatttttact 2880 tttccgatgg gaaaactgag gctcagagca attcagggaattcctcaaga aggacggcag 2940 aggtgaggca cacagaagag agaagagggg ctaaagcaagcctggctagc ttttgcctcc 3000 agggtaggca cgtgggacag gctgtccatc cactgggtcactaggccagc cagggatgct 3060 ccagccccca gtgcccacag cagcgttctc tgtggctgatgagggaccgt gtacctgtgt 3120 gtggagggag ggtggggtct tctgttcccc tttcactgtcaagcccagac cttcttgtac 3180 tttcacctga taagtattta atatacacaa cactaactatggtgtgatga tttaggagta 3240 agtacagcca gatctaagtt caaatactgg ctcccacacaaactgactgt gtagcctcag 3300 gcaagttagt tagcatctgt ctctgagcct agcgccctttccatggaagc agaatgaatg 3360 acacctaccc catagggtgg tctgtcccaa gggtgattgaggttttacat gtaaagagcc 3420 aaactagtgc ctggcatcct ttgaaggctt catagaggaaagttgctcta gctgctgttt 3480 ttctcatgtg acctagctcg aatctgggga ctgtcctgcccataggatac cttacaagtg 3540 gcttgcagac agcctggtct cctgctggtc acccgttaggaagtccagaa gctgggagta 3600 gtaatagcac tagcctcgtg gtgatacagt cccagctagaggacacagga tgaggtggaa 3660 gcaggcaccc acttttgggt ctaaaaggtg atgggtaggcagccgaggct ggggacagcc 3720 atccacagaa ctggaccctc cctccctgat gccattttgcaacccgtatg gatttccatc 3780 atggcacatg ggacacttca ggaccctgaa ttctccatgggaccatgagc tcctataggg 3840 caggaatgaa gttgtgttct tctttgaaac ccctggcacaccgtggtcaa cagatcttgt 3900 ttgactcgta gtggtcaata gatggaatag ttggaatcataaagctcaat agaccccatg 3960 agaacctaga agacaaagta cagtcaagag ctcggactttggagttggct aggcctggac 4020 tgaatctgat tctacaactt aatagctgag agggccttggttttcccatc tgtaaagatt 4080 ataattatta taatgaatac ctacctccta gggatgtaatgaggattaaa agagaaagtg 4140 caggtaaact gtttaacaca gaacctggct catagaacacaatacacatt agctgctatt 4200 attattatta ttattttatt tatttatttt gagacagagtctcactctgt cacccaggct 4260 ggagtgcagt ggcgcaatct cggctcactg caacctccacctatcgggtt caagcaattc 4320 tcgtgtctca gcctcccaag tagctgagat gacaggcgtgtgccaccatg cccaactaat 4380 ttttgtattt ttagaagaga cgtggtttca ccatgttggccaggctggtc tcaaactcct 4440 gacctcaggt gatttgccta cctctgcctc ccaaaatgctgggatcacag gggtgagtta 4500 ccatgcccgg ccttagctgc tattattatc atcatcgttatcatcatcat catcacctcg 4560 tagatatgtc aaggaagatt ccctggagga agtgacatttgaatcaagta tttcaaagac 4620 tagatggtga ataccaggca gtcaaagaca cctgggtttaaaaacatcca gaagaatgca 4680 gtggcttggc aacatcgagc aggaagattg cctgatgagcctgtagggta gctgttgggg 4740 agagagcagc aagacggcct ggccaggcca ggccaggccacgtcaggcag ggcctcacaa 4800 acctcaataa caaatgtgga ctttattctg aggccaaggaaagggcatga aactggggag 4860 tggtgtaatc agatgcgtat ttcagaagat gaagattaacagtgagaagg aaaatgtgcc 4920 acagagggga atagaggtca gttaaaggga gtcagggaaagtgtcctcga gacagtgaca 4980 tcaaaggaat gtgaaaacag caaaggagtg agccaggtggatatccaggg gcagaactgt 5040 taaggcagag ggaacagcat gagggaacag cgtgtgcaaaggcctggagt tgggagtgtg 5100 gctggggtgc tccaggaagg gcaaaaagtc ctgtgtggatggagatatgg gagcaaggga 5160 ggagtggtgg gtcagattgg gtagggcctt ggtggtgattgtaaagactc tggagtttag 5220 accaggcaca gtggctcagg cctgtaatcc cagcactttgagaggccaag gtgggcggat 5280 cacctgaggt caggagttcg agaccagcct agccaacatggtgaaacctc gtctcaacta 5340 aaaataccca aattaaccag gtgtggtggc acaaacctgtaatcccagct actctggagg 5400 ctgaggcagg agaatcgctt gaacccggaa ggtggaggttgcagtgagct gagattgtgc 5460 cactgtactc cagcctgggt ggcagcataa gactctgcctcaaaataaaa taaaaataat 5520 aaagactttt gagtttccct ggagtgagag gaaagccttagagggcttta gcaggagatg 5580 aacatgatct gattttcatt tttaatcctt cctgctatgtggagaatgga ctgaaggcaa 5640 ggtgttttgt atatttgtct gtttcgtaga gacagggtcttgctctgttg gccagactga 5700 agtgcagtgg cacaatcacg gcagccttga actcctgggctcaggcgaaa ctcccacctc 5760 agcctcctta ctctcaccat tgtgccctgc taattttttaaaaaatttat tttgtagaga 5820 tgtggtctca ctatgttgcc taggcaagtc ttaaattcctggtctcaaat gattctcctg 5880 cctcgatgtc ccaaagtgct gggattacag gtgtcagctgccatgcccga cctgtatttt 5940 tttttttaat ggggaaaaag ccttttaata gtatgaggtgttttctggtg tttctaccat 6000 aaagctcttc tgtaaatcaa aatgagaatg taattattgatagagcaatg accttagact 6060 acagtgcaga cttttcatct tacatttggg ctcatgaattttagtataac tgattatgac 6120 agtgtttttt acatagttat gatctagagc agaactgaaaacaaaataac acatactcta 6180 catcaatata ttcgttcagt aatatctggg cttggatgaacctgcagaag taggtaaagc 6240 tgtcagatat tttcttaaac caacagaaaa gaaatgtatatgacagatgt tgtgtttact 6300 tacttattta tttatttatt tatttatttg agatggagtctcactgtgtc accaggctgg 6360 agtacagtgg tgtgatctct gctcactgca acctccacctcccggattca agcgattctc 6420 ctgcctcagc ctcctgagta gctgggatta caggcgtgcaccaccacgcc tggctaattt 6480 ttgtgttttt agtagagaca gggtttcacc atgttggtcaggctggtctc gaactcctga 6540 cctcgggatc tgcccacatc agcctcccaa agtactgggattacaggcat gaaccaccac 6600 gcccagcctg tatttatttt tttaccacta tggagtccaatatgaaattc tcacaactat 6660 gcatatacat tattaacatg taagcacacc taggtataaatatgcacata gtccattaat 6720 tacatcaggg gaattaaaaa catactttca agttaaaatgaattttcagg aaaaaaactg 6780 cattcacaaa tctgaaatgt gaatacaaaa atgaaattgtgaaataaata atgaatatag 6840 gtgtcaccta aacttccata gtaacatgcc tccaaatgtggatttagtga tcatccacct 6900 tgggacaagg gcttttgaga gcctccagct aaattagggttccagtagca gagtggctgg 6960 caagcctgcc ctaatgaata atgccagcga gctgggcgtgggtacttaca gtgtgccctt 7020 catggaatac tttttttttt ttttttggaa tggagtctcgccctgttgcc caggctggaa 7080 tgcagtggca caatctcagc tcactgcaac ctcgtcctcctgggttcaag caattctcgt 7140 gcctcagcct cccaggtagc tgagactaca gccctgtgccatcatgttct gctaattttt 7200 gcatttttag tagagacgag gtttcaccaa gttggccaagactggtcttg aattcctgac 7260 ctcaggtgat ctgcccacct tgacctccca aagtgctgggattacaggct tgagccactg 7320 cgcccggccc atgaaatact tcttacctgg cggacagcctaatagcctag ctgtctaacc 7380 catggctggg ggtccttcac acttgtttat actggcagacgtccctgtga ctcttgtctg 7440 atccatgtcc aagtttatgc ctgtctgacc attgctctggcgctgggagc cagactgtgt 7500 tcccagcaac ccagggaaaa ccaggcctgg gctgggcctgggttcctgag atggaaggtg 7560 caaattcagt acaccacctc aatgcaaaac aagttcaaaggcttattact tacagatcct 7620 gagcagggaa ggtgcaatga gtagggaggg tcatcctccatcctgggcta catgaagcgg 7680 gaatgaagag tcaggcaaaa agaaagtgag agcttgtggcaatgagaagt atattatgta 7740 agggactagg gtgtgggtca ggttaagttt gagggcaaatgcttgaatga tccctttaaa 7800 ggaatgggtg ggaagtgggg agcccagttt gccgggagggagagatgcct cgaagttctt 7860 atctctggcc actggcttgg accatctgag tgtggcatctacttctaatg cctaggcagc 7920 aacctttgct gtgtcatctc ccttacacaa ggttggaagcaaggagaccg gtcaggaagc 7980 ctttggtgta acccatgtta ttgtaatatt cattcatttactcaacagat gtttattgtg 8040 cacctactat gtgctgaggc catggcaggc aggctctggggatgtggctg agaacaggac 8100 agagcccctg gtccttgata tcctcaagga tgctccctcctggaggccat taggttcctg 8160 ttccatggtg ttctgctgga accctccggt cccagagtgtgcaggagcct cccctcctgg 8220 caaagggtct tctctcatgg cacaagggct gcagtacagccagtcagtgg ctcctggttc 8280 ctcaaactca gtgagcactt gcctgccctt cgtgctgcccctcagcttgg gatggcctga 8340 gtcaagacca gccaggagct ccaggcttca tgacccctttctttccccca gggaggcccc 8400 gtctggcccc tccccagaat gtgacgctgc tctcccagaacttcagcgtg tacctgacat 8460 ggctcccagg gcttggcaac ccccaggatg tgacctattttgtggcctat cagaggtaga 8520 ggggactctc tcggctggtg gatgggaaga ctgagggggtgggtgggggc tggaggggct 8580 tctctgggac agctgcaccc agtgtgggca gcactggctagctctctggg ccctacggga 8640 gatggcatgt ggccggcatt tggagagggg cttttgataaaggtctggag gtggggaaga 8700 tgttgaatga agagcagtgt acaggtgacc agtctgccggggcgggggta agtctttgag 8760 gaaagttggt gtggggcatg gatgtagctg tgggggccagaggatgaaat tctcaagtgg 8820 ctggatgagg tgcttggagc tgtcccagct gatcagtgaggcaactaggt acacggcaga 8880 ggagctgtta cctgggcaat taggcatccc tcaatgatcacacttttttt ctcttttttt 8940 tttttttttg agacagagtc ttggtctgtc acccaagctggagtgcagtg gcttgatctc 9000 ggctcactgc aacctccacc tcctgggttc aagtgattctcctgcctcag cctccagagt 9060 agctgggatt acaggcatat gccaccacat ctggctaatttttgtatttt taatacagac 9120 gaggtttctc catgttgccc acgctggtct cgaactcctgagctcaggtg atccacccac 9180 ctcagcctcc caaagtgttg ggattacagg cgtaagccaccgcgcttggc caaatggtca 9240 cacttttccc gatgggatca ttctcaattt ggaagcccaggcagccacag cgaatccaga 9300 gaaatctgac aatggaagca gatccaccat cttcgaacatagatgggaat cgttcagagt 9360 tctttagcag gacagtgaga tgatagaagc agaagctcgggaggattcac ctggagttgg 9420 tgaggagggg aaagcaggaa gaggagggga ccaccgtgtcctcaggaccc gtcctgtgcc 9480 aggccaagtg ctaagggccc tacgtgaata tttcacttccttctcccaat gtgaccaggc 9540 aggctctgtg ttttccccat tctagaggtg aggggattgagctcagaggg tgctgtgtct 9600 tgtctgagga aggacgtcat ggagccagaa ggggaactcgggtccgactc caacatttgt 9660 gcccttcctg ttgcatcacg tcatccttcc atgtgtggaatccacatgtg agtgatggga 9720 gcctggcttg agcagggaca gactgcaaga gagctttcaaaagcaagagc gttatcaggt 9780 gccagaaaac acctaatatt tactgtgtgg ctggcactgtgtcaacacat gtaatgaact 9840 taatctcaca gcagctctct gaggacaagt tcagtacgcctctttacaga ggaggagact 9900 gaagcaccaa gggtgcatgt tgctcaaagt cacacagctgggcgtagtat ggctggaata 9960 aatttattaa ggagttgaaa gtctatcctc taggaccaagcatggtggct tacatctgta 10020 atcccagcac tttgggaggc cgaggtgggt ggggagattgcttgagtcca agagttcgag 10080 accagcctgg gtaacatggt gaaaccctgt ctctacaaaaaaaaaaaata caaaaaatta 10140 gtgaagtgta gtagcatgtg cctgtgttcc cagctacttgggaggctgag gtggggagga 10200 tcacttgagc ccaggagatg gaggttgcag tgagctgagatcacaccact gcactccaac 10260 ctgaacaaca gagcaagatc ctaaaaagaa agaaaatctatcctctgaac ttctatgata 10320 tttttcatgt cttttataca ttagaatggt gatattctaattatataatt tttttcattt 10380 gttagttgga attattttat aaagagatgt atcctctcatctggtatttg atatccagtc 10440 atactattca aataggcaag agaggataaa tgcttaatttttttccttta tcaattttca 10500 agataatgaa ttggttcctt atcatctccc aaaggtgattgctagtttat tattatcatt 10560 atgaactcag gcatttaaac acatttggtg gtttcagtctattgcgacgt actctgctca 10620 ttgaagcttg aattgcctca tctctgtcca gtgggagtctcatcaagttt gctcctgagt 10680 ccttttaact tgaccctagt ggtcaagtta aatctttccagatttaacag atacctttcc 10740 agctgtccat tacgacaaga tgttccaggt ccctctggtacaattcctga cctaaaacct 10800 gcagtcagcc atttctccat ttagtaagaa atggttataaagactataat ctgcatgcta 10860 gctatgctga tcactactta gctattgctt ttggtgttttcagtgaacag agtgatgtgt 10920 gtataccaca tagacacaca catgtacata ctttttttttttagacagag cttcactctg 10980 tcacccaggc cagagtgcag tggcatgatc tcggctcactgcaacctcca cctcctgggt 11040 tcaagagatt atcctgcctc agcctactaa gtagttgggattacaggcgc ccaccaccat 11100 acccggctaa tttttgtatt tttagtagag acggggtttcaccatgttgg ccaggctggt 11160 gtcgaactcc tgacctcaag tgatctgccc ccctcggcctcccaaaatgc tgggattaca 11220 ggcatgagcc atcgcaccca gcctacatgt acataatttttaagataaaa tgcctaatga 11280 gttatacggg tgcttcccat ctaaatttag ttccttaggatttttacctg acttctatgg 11340 tacatctata ttttctttct ttcacactga gaatcctgtttctcaaggac aggggacatg 11400 atagaactag aatgacccat aattactcat tttctttatcccaaaacata catacttgcc 11460 tcttaatagt ttcttgctct tttcgcccaa agggtttgtgatggtcaata ttaggtgtca 11520 acttaattgg gttgaaggat gcctagatgg ctgttaaagttttgtttctg ggggtgtctg 11580 tgagggtgtt gccagaggag actgacattt gagtcagtggactgggaatg gaagactcgt 11640 cctcactcag tgtgggtggg cacaacccaa ctggctgccaggctggctgg aaagcaggtg 11700 gcagatggtg ggatagcttc gcttgctggg tcttccagcttccttctttc tcccgtgcgg 11760 gatgcttcct tctgctcctc ctgcccttga acatcacactccgggttttt tggcctttag 11820 actcttggac ttaagttagt ggtttgctgg gggctctcggatctttggtc acagactgaa 11880 ggctgcactt tcagcttccc tggttttgag ggtttcagattcggactgag tcactatggc 11940 ttctttcttt cccaccttgc tgacggccta tcgtgggacttcgccttgtg atcgtgtgag 12000 ccaattctcc ttaataaact ccctttcata tatacgtataacctattagt tctgttcctc 12060 tggagaaccc tgactaataa agggttgttg ctttttctttaaaatctagt aattttattt 12120 gactgtgtgt tggtattgct cattcattct gagttgatatttttaggcac tcaatattct 12180 cacttaatac atggttccaa ggcattttta ttttaggaaggttttcttaa attatagttt 12240 tagtatttgt tctattctct tgttttgatt ttcttctttagggactcata tcacttgtat 12300 gttggatctt ctttttctgt gttcagtatt tgtcttttgggcacagagac tcacacctat 12360 aattccaaga ctttgtgagg cataggtagg aggatcgcttgagcccagga gtttgagacc 12420 agcctgggca acatggtgag gccctgtctc aaattaaagaaaaaggagag aatacttgtc 12480 tttttctttc aaatgccttt tatctgtctg tctatctactattctgctct ctaaatgaaa 12540 taggtttcac tcttgagttt ttaaaaaact gtgtgcttccatgtgtgaga ttattcaaca 12600 tcttatttgt aatctttctc ttggttacat ttatttttcctgaaactcta gtctgctttt 12660 agctgacatg tttgtagcta agagcgcaca tttcttatcatagcttgccg tgctgaatta 12720 attccaattt tcttttaaaa ccaacattat tgagttaaaatgtatataga ataaactgtt 12780 cccattttaa agtatacaat ttgatgagtt ttgacaaaagtgggcaccca cgtacccacc 12840 accacaatca agatgtaaga cgttctctat caccccagaaagttccctca tccactttgc 12900 attcaggcct ccagatctag gcaaccacag atctgctttctgacactgtg gattaaactt 12960 tgcctgttcc agaatttcat ataaatggat gtgtatagtatgtacccttt cgtgtctggc 13020 tcctttccct cagcataatg tttctgaaat tcacccacattgttacatgt atcagtagtt 13080 aattcctttt tattgctgag tagtaatgcc attgtatgactatgtatgac atttgttaat 13140 ccattttccc gtcagtggat atttgggttg cttccagttctgggcaggta ttcatttgct 13200 agggctgcca tatgcttgcc ctctggcctc ccaaaatttgtgtccttttc atatgcaaaa 13260 tacattcacc ccctcccaac agccccaaaa ctctcttttttttttttttt tgaaacagag 13320 ttttgctctt gttgcccaag ctggagtgca atggtgtgatctcggctcac tgcaacctct 13380 gcctcccggg ttcaagagat tctcctgcct cagcctcctgagtagctggg attacaggca 13440 tgcgccacca cgcctggcta attttttata tttttagtagaaatggggtt tcaccgtgtt 13500 agccaggctg gtcttgaact cctgacctca ggtgatccgcctgccttggc ctcccaaagg 13560 gctgggatta caggcatgag ctactgcacc tggctagccccaaaactctt aacccatttc 13620 agcatctact ctaagtccaa agtctcatct aaatcaggtatgggtgtgac tggaggtgtt 13680 actcatcctg aggccaaatt cctctccact tatgaacctgtgaaaccaga caggttatgt 13740 gctttgaaaa taaagtgatg ggacatgcat gggatagactttcccattcc aaaagagaaa 13800 aataggaaag aaggaaagag tgacaggtcc caagcaagtctaaaacctcg cagggcaaat 13860 tccattagat tttaagtttc aagaatagcc ctctttggctcagtgctctg ccctttgggc 13920 ccactggggc ggcagcccta tcccctttgc cctgggtggtgaccctaccc tcgagtcact 13980 ggttagcagc agcctagcct gctgaaacta aggaggggacagtgttgcct ccaggtcttt 14040 ggtggcagtg acaaccctgc tgatctctga atcatcttccaggaaatttt tccctatact 14100 tgaaggatat tgcgtgttca cagccaaata gctccagctcttgtcccttt ctttagaatc 14160 ccagaagtcc aacagccttc cttcattctg tcccatctctgtccccttta gtcaaagctg 14220 gaagtgcctc tgctggtata atcccatcag tatgtctaatttctgcttaa atggctgatt 14280 aagtctatga gttgcacctc tgatctcttt atcaaaaggttgttctagcc acaaccttag 14340 tgtcctcccc agaacatgct ttctcatttt tttttttgcaatgtggatag gctgaaaatt 14400 ttccaaagct tcaagttcta gttccttttg gcttaccaattcttttcata tatctcttct 14460 ctcacatttt actataagca gtaagaagaa accaggttgtaccttcagca ctttgcttag 14520 aaatctcttc tgctaagcat ccaagtttat gtcttttaaattatcttttt gttatttatt 14580 ttatattatc atttttgaga tggctagcca atgatcttttaacttctaat ttctgcaaaa 14640 cactagaaga caattcaacc agttctttgc cactttataacaaggatcac ctttcctcca 14700 gtttccaata acacattcct cttttccacc tgagacctcaccagaatcac ctttaatgtc 14760 tatattccta ccaatagtct ttttaaggca atataggctttctctaacat gcacttcaaa 14820 cttcaagatt ctacccatta tgcaattcca aagccacttccacattttta ggtattgatt 14880 acctcagcac ctcatttctg gtgcccaaat ctgcactggtttgctagggc tgccataaca 14940 aagtacgaca gtctgggtaa acaacagaat tttattttctcaaaattctg gaggttggaa 15000 gtccaaggtc aaggcgttgc taggtttagt ttctcctgaagcctctctcc ttggctagca 15060 gatggctgcc ttcttgctgt gtcctcacgt ggctttttctctgtgtgtgt tcactctggt 15120 atctcttcct cttcttacaa gtacaccagt cctactggattagggcccca gccttattac 15180 ttcatttaac cataattacc tctttaaagc tcttatctcaaaacacaata ccactgggga 15240 tgaggtcttc aacatatgaa ttttggggga actcaattcgtccataatag ggctattatg 15300 aattaagctg ctgtgaacat tcatgtacaa gtctttgtgtggatatgttt tcatttctct 15360 tagataaaga tctaggagta tcagcctggg caacatagtgagaccccatc tttacaaaaa 15420 attttcaaaa ttagccaggc atggtggcgt acacctgtagccctgccatc tcaggaggct 15480 gaggtgggag gatcccttga gcccaggggt tttagactgcagtgaactat gattgcacca 15540 ctgcacccca gcctgggtga cagagtgaga ctctgtctctaaaaaaaaga gagagagggg 15600 aggaaggaaa gaagaaagag agggagggaa ggagggagggagggagggag aagaaaaatg 15660 gatctagggt taagatttag gagattaggt aatgaatgtgtactattaca gggaactgtc 15720 gagctgtttc caaagtgact gtaccattgt tcattgccaccaacaataca tgagagttct 15780 agttactcca tgtgcttgtt acacttagta ttatcagtctttttcatttt aaccattcta 15840 gtgagtatgt agtagtattt tattatggct ttaatttacaactccctaat gatgaatgat 15900 gttgaacatc ttttcatgtg cttattggcc attcatatatcttttgtgaa gtgactattc 15960 aaatattttt ccacttttta ttaggtcatt tattttcttattattgagtt atctatgaat 16020 acaaatcctt tatcagtgta tgtattgtga tttttttccccagtggctgg ccttttcatt 16080 ttcgttaggc ttttttggtg ggtttttttt tttttttttggaagagaaaa atattttaat 16140 ttgataaaat ccagtatatc aggtgttata gactgaattatactctaccc cacaaattca 16200 tatgttgaag ccctaacctc taagtgacta tttggagatgagcctttaag gaggtaatta 16260 aagtaaaatg agatcataag ggtgggccct aatctaataggactggtgtc tttataagaa 16320 gaggaagaca ccaagagcgc atgcacacag aagaacggccttgtgaggac acagcaagat 16380 gacggccatc tgcaagccaa ggagagaggc ctcagtagaaaccaaacctg ctgatgcctt 16440 gatcttggac ttccagcctc cagatttctg ttgctgaagccaccctgcct gtggtgtctt 16500 accatggcag ccctcacaga ctaatatatc agatttttttccttcaacag ttaacgcttt 16560 tggtgtccta agcaatattc gcctgaccca gggtcatgaagatttttctt ctatgctttc 16620 ttctggaagt tctataattt tagcttttac atatttttttaactttcctt cttcttgcct 16680 tctgtttctt ttaaggcatc atctattgtg ttaatttgttcttgtattcc ttctgattta 16740 ttcttcactt ctgaaatgaa ttttgctttt taaaaatatatataattctt ttctgtgtct 16800 gagtttttct aattaggttt tatgtggttt tttcttgtcctgcatcactt tttactgtct 16860 tttgcccatt ttgaagtatc aggttccagt tttgatctgttcatggatat gtttttgtga 16920 catgtttctt ctggcttctt atcatttatt gcttagcttattaatttcta ttctttctta 16980 ttttctatta taagtattta aagctatatg ttttcctctaagtattactt agctgtctta 17040 tacgttttca tttgtgttat ttggtgatca ttcactttcagctatttatt aatttccatt 17100 ataattcttt catctatggg ttgttttaaa aaatatttttaaggccaggt gtggtgactc 17160 acatctgtaa tcacagcact tagggaggct gaggtgggaggattgcttga ggccagaagt 17220 ttgagaccgg cctaggcaac aaagtgagac cccctctctacagaatattt ttttaaaatt 17280 agctgggcca ggcgtggtgg ctcatcccag cacctgtaataccagcactt tgggaggcca 17340 aggcagatgg atcacctgag gtcaggagtt cgagaccaccctgggcaaca tggtaaaacc 17400 ccatctctac taaaatataa aaattagcca ggtgtggtgataggtgcctg taatcccagc 17460 tacttgggag gctgaggcag gagaattctt tgaacccaggaggaggagtt tgcagtgagc 17520 cgagattgca ccactgcact ccagcctgga tgacagagcgagactctgtc tcaaaaaaaa 17580 aaagaaaaga aaattagctg ggtgtagtgg caggtacctgtggtcccagt gactcagaga 17640 ctgaggcagg aggatcacct gagcccagga gtagaggctgcagtgagcta tgtttgtgcc 17700 actgcactcc agcctgtgca acagagcaag acgctgtctcaaaaaatata tattttttta 17760 aattttcaaa cttcctttag ttctcttttt gttattaacttttaactgaa tgttttgcaa 17820 tcagaagaaa tactttatga gatacctatt ctttaaaatttcttaagaat tgctttgtgt 17880 taatattttg ttaatagttc acatgtggtt caaccaatttgtttagttag ttctgtatat 17940 gttcattaga ccaacttgat aactgtgttg ttctttatttatttatgtat ttatttttct 18000 ttgtctattc atcaattgct gggtgagatg tattaaaatttcttgttgta agtgtggctg 18060 ttcactttct acctgtagtt tgtctgtttg ctttatagagggtgaagttg tttagtaggc 18120 acacataagt tagaattttt ctgtcttcct ggtgaatggaatcatttatc attatctaat 18180 gttcttttca tctttagtat tgctttggac ttggaagtctgtattttgtc tcctgttaat 18240 ataactacac tggttccttt ggtgtgaata tttgcatagtataacatttt ccatgaagaa 18300 acaaaacaga ggaattggtt ctttctcaaa atctgatctttgtgtcagcc cccatctcag 18360 ccttctccat tcatccttgg tcactcccca aacccaggagcaatccttga ttctcctttt 18420 ccccacattc tacatccaat ccgttagcaa gttctattagttctattatt acctccaaaa 18480 tagatattga atccagccct ttctcactgt ctccaccatcatcctgtctc acatccctac 18540 catggcctcc ttgctggttg accagagtga tcttgtaaaaacatgttagg ccaggcacgg 18600 tggctcctgc ctgtaatccc aacactttgg gaggccaagcgggtgggtca cctgaggtca 18660 ggagttggag accagcctgg ccgacatggt gaaaccctgtctctactaaa aatacaaaat 18720 tagccaggtg tggttacgct ggcctgtaat cccatctactcgggaggctg aggcaggaga 18780 atcacttgaa cccaggaggc ggaggttgca gtgagccaagatcatgccac tgcaccccag 18840 cctgggcaac agaacaagac tccatctcaa aaaataaaaattaaaataaa atgttaggct 18900 ccctgggtct ctggcttagt ccatttgtac tgctttaacaaaatacctta gaatggtgta 18960 attctaataa ttgctattaa taaataatag caattaataaataatagcaa tttccttctc 19020 acagttctag aggctgggaa gttcagggtc aaggtggcacctgactccgt tctggtaagg 19080 gcggctctct gcttccaaga tggtgccttc tcgctgcgtcttcgcatagc ggaagggcaa 19140 acactgtgtc ctcacgtggc agaagagata gaagggccaggcagctctct gaagtatcca 19200 ggttggagtc atggacctgc atgttcccct ctgacatccacagagtacct atcatggtcc 19260 ttggcatgca gcaggtggcc cataaacgcc tgaatgaacaaacatatagt aatggtcgct 19320 agtactagga atagcagcca ccgcaacagt cctgtgagggaggcattaca gatgaggaaa 19380 ctgaggttta ggggcaagga cctgcccatg gtcccaaagctagggaggga cagggctggg 19440 attcccactc ccatccatct ggctccagaa cctgagctcctgaccaggct gttcttatcc 19500 tgtctcagcc agtggctgcc tgtctggacg gatggacctaaagtcagtcc agccaaacag 19560 agggaagcat gatcaactgt tctctaagtt ccctgacccggagaggctga gtccatggcc 19620 caagctctcc tctctcctcc cccagctctc ccacccgtagacggtggcgc gaagtggaag 19680 agtgtgcggg aaccaaggag ctgctatgtt ctatgatgtgcctgaagaaa caggacctgt 19740 acaacaagtt caagggacgc gtgcggacgg tttctcccagctccaagtcc ccctgggtgg 19800 agtccgaata cctggattac ctttttgaag gtaggtctgtgggtaaggga ctgagtggaa 19860 ggctgtccat cccatcgggg agctgtgctc agtgctcagtggttctgttc tcctgaccat 19920 ctgtctccca cttccccaaa gcagagggca gctccctgggccaggccctt tgagatgggg 19980 tgtgggacca gcaacagcga gggaccatgt ctggcagcctgtcagggagt taggggagct 20040 ccagccagca ccagcaatct cacgtgcacc ctctgctaacaatgttcatt attttcagtt 20100 gagcaccatt ttggtcatgg actacacaag gcactttatatgcttattcc tattttttta 20160 tgttcagctt ctctccttaa aaacaatgtt taaaaccaattctgggccag gcgtggtggc 20220 tcacgcctgt aatcccagca ctttgggagg ccaaggcaggtggatcacct gaggtcagga 20280 gtttgagacc accctggcca acatggcaaa accccgtctttactaaaaat acaaaaatta 20340 gccaggcttg gtggcaggca cctgtaatcc cagctactcgggaggctgag gcaggagaat 20400 cgcttgaacc caggaggcgg aggttgcagt gagccaagatcacgcccctg cactccagcc 20460 tgggcgacag agcgtctcaa aagaaaaaaa ttaataaacaaagaaaaaaa aacaaattct 20520 gtttgcaaaa gtattttcta tacactgtag aaatttgtggggtgtggggg ggtaaagatg 20580 atagaaaaaa aaatgtccca tgcttactgg cagaaatcatgtattgacat tgggtgagga 20640 gggcactttt tttttttcag tctattttta atcttcacagcaaacttgtg aggttcattt 20700 ccatcaacct gagactcaca gaagctaaga aacttgataccgctagtaac cagtggactt 20760 gataccgcta gtaaccggtg gacatagatg tgaactggatctttctgacc tcgggcaggg 20820 ccgggtaaca aggggaggat aaatgcccag acagtgtcctcagagagctg agagctgtaa 20880 cttgctgccc gggcttctca cagtgttcaa ggacaaaataaggctttaag agagaagagg 20940 gacagactga ttgcagggca gcaggaagag atggtagagaaggaagaaga gatgattcgt 21000 gtggaaagaa gctggctcgg tggatggata aaagaagggaaggacagatg ggtaagaaga 21060 aagggaggat ggaggggatg gaggaggaag caatggaaaaatgggaagga aggaggttgg 21120 atggaaggat agatgcctat taggaaggaa atatgtgtggatagagagat ggaggatagg 21180 aagtatgtta gtcaaggttc tccagagaaa ctgaaccaataggatatata cagatacact 21240 aagaggaggc cagccgggcg cggtggctca agcttgtaatcccagcactt taggaggccg 21300 aggcgggcgg atcacgaggt caggagatca agaccatcctggctaacaca gtgaaacccc 21360 gactctacta aaaatacaaa aaaaaattag ttgggcgtgatgatgtgcgc ctgtagtccc 21420 agctgctggg gaggctaagg caggaggatg gcgtgaacccaggaggcaga gcttgcagtg 21480 agctgagatc gtgccactgc acttcagcct gggtgacagagcaagactcc gtctcaaaat 21540 aaataaataa ataaataaaa agaggccagc catggtggctcacacctgta atctgagcac 21600 tttgggaggc cgaggcggat ggatcatttg agatcaggagttcaagacca gcctggccaa 21660 catggtgaaa ccctgtctct actaaaaata caaaagttacccgtgtgtgg tggcacacac 21720 ctgtagtccc agctactcag gaggctgagg caggagaattgcttgaactt gggaagcaga 21780 ggttgcagtg agctgagatc acgacactgc actccagcctgggtgacaga gcaagacttt 21840 gtctcaaaaa aaaaaaattt ataataagag gagatttattatgggaattg gctcatgcaa 21900 tcacagacac aaaaatgtcc cccagcatgc agtcatgggctggacaacca ggaaagcttg 21960 tggtgtgatt ctgtctgagt ctgaaggccc aaggccaggggagcagtggt gtaaccccca 22020 gtccgaggcc acaggcccga caatcagagg ggccactgatataagtccca gagtccaaat 22080 gccggagaac aggaagctcc aacgtccaag gacaggagaagttgatgtgc cagctcagga 22140 agagagaatg tgaatgtgcc attcctcctc cattttttgttctctttggg ccgtcagtgg 22200 attggatgat gcctgcccac actggtgagg acagatcatcaccaaatctg ccgattaaaa 22260 tgttaatctc ttctggaaaa atcctcacag atgggcccagaaataatgtt ttactgtcta 22320 cctgggtatc ccttagtgca gctaaattga cacataaacttaaccatcac aggccaggca 22380 ctgtggctca cacctgtaat cccatcactt tgggaggccaaggtgggaag atcctttgag 22440 gatgaggtag gcagatcact tgagcctagg agttcaagaccagcctaggc aacataggga 22500 gacctcgtct ctacaaaaaa aaaaaaaatt taaattcgctgggtacggtg gtgggcacct 22560 gtggtcccag ctatctggga ggccaaggta ggaggatgacttgagcccag gaggtcaagg 22620 ctgcagtgag ccatgattgt tccattgaat tccagcctcggtgacagagc aacaccctgt 22680 cttaaagaaa gaaaaaattt aaccatcaca gaaggcagaagaaaaggcag atgggtggat 22740 gagatgggtg ggtagatagt atagaagaaa agcgggacatccaggcaggg aaggaagggc 22800 tggagcgaag gagaagcaag gaaggaagga aggagagacaagaaggaagg atgtgtagaa 22860 aggtggaaga gaaaagaaga atggatgtat gggaagaatggatgagtagg ttagaaggct 22920 cactggctag ataaaaggtg agaagtataa atgaataataagaaaggagg cataggaaga 22980 aaaaaatatt ggttagaaag gatgattgag aagaaagggtggttgggaag gaaggaagga 23040 aggatggatg gatggatgga tggatgggaa ggaaaggaaggataagaagg cagacaggaa 23100 ggctctctgg ctagaagaat ggcagacaaa ccacaataattgctgaatgg gtaggaataa 23160 gacattagaa gaataaaggg aaagacacaa agatatttaaaatgttttca ttaatttttt 23220 gcctcctccc tgaatttctc ctgattcttc agccccacatcccaagccag ggtgatcctt 23280 cctgccttta cactccctcc acactttttc tgctctcatatgtggccgtg gtcactttct 23340 tttggtagtt tgcatatttc atttacccca aactttcagctcctgaaggt caggatacaa 23400 ggaggcctca tctccgcatt cccctcagct cccttcctgaagcttgatac ctagtcagta 23460 cccagtggat gtttcctaaa catgtaagta atgacatcatgaagaagcca catgtttacc 23520 ttgaccacaa acacagggca aaggtgacta gtgtggtcagagatccctgc tggctgggaa 23580 tcagggaagg ctgcatggaa gaagtggcat tttagttagaacttgaaagg tggtgtattt 23640 agttttctct ggctgccata ttccttgtca cattgccctctccatcttca agccactggg 23700 caaggctaga aggccctcaa cagactatcg gtaggaatgtggaagttgaa gactcagagt 23760 gcagaaagaa acaagtagca ttttagagaa aagctaaatcccctccaaga atacctcaat 23820 catcgtgaag agcctgttag tagacgcact aacactcaaggcactgcttc acaaggtaag 23880 gaacgtgtaa ttgaaaactt gagaaaggaa gaaacttgttctgtactggc agaaagctta 23940 gcagaattgt gtcctgcagt catatgggac acagagcttgtaaatgatga atttgaatgc 24000 ttatccgaga aggtttccaa ataaaatgtg gaaggcacggcctggtttct tcctgcctct 24060 tatagtaaaa tgcaagagga gagagagaaa atgagggaagaacttaaaca gaaaggaacc 24120 aggacttgat gatttgggag gttctcaacc tatgcaaaaaacaataaaat taagagattg 24180 tagctgggca cagtggctca tgcctgtaat cccagcactttgagagtccg aggcgagcag 24240 atcacctgag gtcaggagtt tgagaccagc ctggccaatgtggggaaact ccgtctctac 24300 taaaaataca aaaattagct gggtgtggtg gcgggcacctgtaatcccag ctactcagga 24360 ggctgaggtg ggaggatcac ttgaacccaa gaggcggaggttgcagtgag ccaagatcat 24420 gccactgcac tccagcctgg gtgggtgaca gagcaagactccatctcaaa aaaaaaaaaa 24480 aaaagagatt gctcccaaaa gtgtgacata gagaaacagccaagtatgtg attataccaa 24540 acttcaggaa gataaaagat caaagtactc agtcgctcaaaaggctcttt gaagagatta 24600 agattataac tcacagtccc cttcaatcaa accaggggacttctaggaag ctgaacagca 24660 ttgtccctca gccatatcag ctggagccaa aagtagagaagggcttatct gaaaaaagga 24720 tctgtggacc tggcttttat ctaataatgc agtggattcccccatgacat ccataggaga 24780 cccgtaaagt tcctgagacg tttacatcca cagaaacactgttagcttgg attaaatgga 24840 acacagagag tatgaaatca aagaaggctg ttggactctccagtttctac tgttgagatg 24900 cagactggta aaactactta gctgcaaaca cctgctacctttagtgaaaa ggaaggatat 24960 ctcagacggt gaaaccagaa gctcaaaggg cagtgctaagagcgaaagag aattcttccc 25020 aggccttgaa acctaatgga gttttcttgg ctggattttcaaactgcatt ggaccatgac 25080 ctgattgtcc ctttcatgtc cccatgcttg agccagattgtctgcaactg ttatcctgtg 25140 cctgtcccac attttatgtt gggagcagaa aactttagttttgctggccc acagatagag 25200 agaaactgta ccccgagagt tgtactgact ggactatgcccagagtctat ttgactctga 25260 cttagatact gttgatttgg gaatttgagt tgatgctgtaatgagatgag actttggggg 25320 acattgggat ggagtgaatg gattttgcat ttgaaagagatgtgggttgg gtaatcctag 25380 cccacacctg taatcccagc actttgggag gccgaggcaggcagatcacc tgaggtcggc 25440 agttcgagac cagcctgacc accatggaga aaccccatctctactaaaaa tacaaaatta 25500 gccaagcatg gtagcacatg cctataatcc cagctactcgggaggctgag gcagtagaat 25560 cgcttgaacc cgggaggcag aggttgcggt gagccgagatcacgccattg cactccagcc 25620 tgggcaacaa gagtgaaact ccatctaaaa aaaaaaaaaaagaaagaaag agatgtggat 25680 tttgggtggg ggacagaggg aagaccatgg taggcagaatgatcctctaa aggtgctctg 25740 ccctaatccc cagaagctaa gaatatgtta gatgtcagtattgcgtggca gtaggaatct 25800 taattaacgt tatagactgt tatggtttga atgtcccctctaaaactcct gttgacattt 25860 aatcatcatt gtgattgcat taagaagtgg ccctgttaaaaggtgattta gtccttaaga 25920 acgctgcccc cgtgaataga ttaaggtcag tcttgcgggagtgtgtttat caagaatgga 25980 ttgttaaaaa gtgagttctg gccaggggca gtggcttatgccactcagca ctttgcgggg 26040 ccaagacttg aagtcagttg tttgagacca gcctggccaacatggtgaaa gtctgtctct 26100 actaaaaaat acaaaaagtg tccgggagtg gtggcgggcgcctgtaatcc cagctgctca 26160 ggaggccgaa gcaggaggat cgcatgaatc cgggaggcagaggttgcagt gagctgagat 26220 cgccccgttg cactccagcc tgggtgatag agcaagactctgtctcaaaa aaaaaaaaaa 26280 aagaggaaag aaagaagaaa gaaagagaaa gaaagaaaagaaagaaaagg aaggaaggaa 26340 ggaaggaagg aaggaaggaa ggaaggaaag aaagaaagaaagaaagaaag aaagaaagaa 26400 agaaagaaag aaagaaagaa agaaagaaaa gaaagaagaaaaaaagaaag aaaaaagaaa 26460 gaaagaaaaa gaaagaaaga aagaaagaaa gaaagaaagaaagaaagaaa agaaaagaaa 26520 agtgagttct gccctctctt gctggcttac tctcaccctctcttgccctt ccacctgcca 26580 ccatgggatg acacagcaca aaggccctca ccagatgccagtgccatgct cttggacttc 26640 caagtctcca gaaacatgag ccaaatacac ttctgttcattataaattac ccagcctgtg 26700 atattctgta ataacaacac aaaatagact gagacatagatcttcaaata gtgaggttat 26760 cctggataat ccagatgggc ccaatctaat cccatgagcctttaaaactt tctccagatg 26820 gaggcagaag agaagtggca gaaggggaag tcagagagatttgaagcata aacaggactc 26880 catggtgccg tttctggttt gacgatggag tggtaacgtgatgaaaaatg tgggtgcctt 26940 ccggagctga gaggctccca ctaacaatcg gccaggaaacagggaccaca gccctacagc 27000 cacaaagaac taagttttgc tgacaaccca agggggcttggaagtgtctt ctcccccatc 27060 ggttccagat gtgagaccca gagcgaagga accagctgagcccacctgga cttctgacct 27120 agagaactgt gagataataa gtttgtatca tttttaaggcactgtgtgtg tggtaatttg 27180 ttatgacagc aatagaaaat gaatccagat gggcaggatctgccaggcca gtgacatgtg 27240 gagggcaccc aggcggatgg gatggcatga gagaaggcaggtcagcaatg agcttgccca 27300 ggtcacctct cctctctaag cctcagtttt cctctctatgaaatgagagt agtgatatct 27360 ccctcccagg gtcagtgcaa ggctgaaata acagattataaggtgctagg tgcacaagaa 27420 gtgtttgaaa catgctagtt gcttttccat ttccaagagagctctctggt cttgggggat 27480 ggaggcagtg cggcccctcg ggattactga caggtcctgctctgtttctg cagtggagcc 27540 ggccccacct gtcctggtgc tcacccagac ggaggagatcctgagtgcca atgccacgta 27600 ccagctgccc ccctgcatgc ccccactgga tctgaagtatgaggtggcat tctggaagga 27660 gggggccgga aacaaggtgg gaagctcctt tcctgcccccaggctaggcc cgctcctcca 27720 ccccttctta ctcaggttct tctcaccctc ccagcctgctcctgcacccc tcctccagga 27780 agtcttccct gtacactcct gacttctggc agtcagccctaataaaatct gatcaaagta 27840 tgatgaccta caggaggcct gcttgccaag tcaacagattcagtacagaa aaactgaaaa 27900 atacagataa gctctaagaa gcagaccaaa agtacccagagatgaccgca catcactctg 27960 gtgtatatcc aatttcagat ttgttttctg tgtatgcatgtgtgtatagc tgcatttatt 28020 tatggcaagg gctggcagac tttcccgaag aaggccagatagtcgatatg tttggcttca 28080 tgggccgtat gttcgctcag gactactcaa cgctgcagttatagcacaaa aggagccgta 28140 gcctatacgt aaatgaatgg gcatcgctgg gttccagtaaaactgtttac aggccaggtg 28200 cggtggctca tgcctgtaat ctcagtactt tgggaggccgaggtggtggg aggattacct 28260 tagcccagga gttcaagacc agcctgggga acatggtgaaacattatccc tacaaaaaaa 28320 aaaaaagctg ggtgtggtga tgcatgcttg tggtcccagctgcttgggat gctgaggcag 28380 gaggatcgct cgagcccagg aagcaaggcc acagtgagccatgatcgcac cactgcactt 28440 tagtctgggc aacagagtga gaccttgtct caaaaaaaacaaaaaataaa actttttaca 28500 taaacaagtg gccaaccaga cttggtccct gggcctctgctcttgaatgt tcttgcttcc 28560 actaaagtaa cattcacact cccgattttt gcatactctgggttctgggg aatatagatc 28620 cgaatccagc gtggttcctg ccttcaagaa cctcacaaatattctagacc agcactgccc 28680 aatagaaaga aatataatgc aagccacatg tgcagttttaagtgttccat gttaaattaa 28740 gtaaaaagag acgggtaaat cgaattttaa taacagattttacttcatcc aattgaatgg 28800 tatcatttca atgagcaatt ctgatagtga ttgagatcttttacattctt tttcactacg 28860 tctttaaaat ctgatgtgtg ttttgtactt ggaacacttctcagtgtgga ccagatgcat 28920 ttcacatact cagtagtcac gcgtggccag tgccttccataccacacagt gcagcatctg 28980 tagaggtttc ctccactgct gatagactag gagaccccaagatggaaagc ctgaagaatc 29040 tgctcctcga agtagggacc ttaatggggt gcacgccagggcgaccccaa gtggtaggct 29100 gcttttgaac catggctatc cctacctcta gactcagctgaaaagaactc aggtagtctt 29160 gggaagtgct tcctcaatgc ttaaacttta atgcaggaaaagaatagaaa gttcaggcaa 29220 ggagggagga tcacttgagg ctgggagttc gagaccagcctgggcaacag caagaccttg 29280 cctatacaaa aaataatttt aaaaaattac ccaggtatggtggtgtggat ctgtagtccc 29340 tagttacttg gagagctgag gtaggaggat cgcttgagcccaggagtttg aggctgcagt 29400 gagctgtgat cacaccactg cactttggcc tgggtgacagaaccaaaccc tatcccctac 29460 aaaaaaacaa aaaaaaaaaa caaaaaaaaa caccctaccatgtctgccaa ccccactctg 29520 tcctggctgt gtgaaaccag tccccacagc agctctgccactctctgctt cttttccaaa 29580 cagaccctat ttccagtcac tccccatggc cagccagtccagatcactct ccagccagct 29640 gccagcgaac accactgcct cagtgccaga accatctacacgttcagtgt cccgaaatac 29700 agcaagttct ctaagcccac ctgcttcttg ctggaggtcccaggtgggta tcaagtggtg 29760 cagaaggaga aactttccct ctgggccttg ggagcttcgtgacacagtgg ttaagaacat 29820 gagcctagag atagactcgc ctggattaaa accacactcattgtgtgtct ttgggcagct 29880 tacataatgc cccgaacctt ggtttgcaca gtctgcaggatgggtttatt cttgtgagga 29940 ttaaataggg tcatgtatgt gaagcactcg gcacaggtgcagttgtagac aagagccatt 30000 gttgtttctc tcattgttat ttttccttcc ttagaagccaactgggcttt cctggtgctg 30060 ccatcgcttc tgatactgct gttagtaatt gccgcagggggtgtgatctg gaagaccctc 30120 atggggaacc cctggtttca gcgggcaaag atgccacgggccctggtata gcaaatctgg 30180 gggtgtgcgg caggtgggga ggggttgaga gtaagggagtggggctggag ctatgagttg 30240 ttcagataga atatcaagat ggtccagact cttggaccaaaacatctatc tttgtgtctg 30300 aatttccacc attagtaatg cattcattta gtcctgaataaaatggcaaa caggccctgg 30360 agggagcagt gccttaagtt cctttgagat aaataacttcacctctgcta aggatgtgtc 30420 agctgctgag agcagagccc ctggccttgg acctcaggagagacactcaa aaggggagga 30480 gaggaggcac caaaggggac atcttaaaag agttccaatttttagttcac actttaaccc 30540 aggataagct gtgtcctggc tgaccttgga gtttcttccctggtctgctg ggtctctccc 30600 ttagaaccta ggggcgagct ggggcagggg aagcccaggaggtgatatag gtcggccctg 30660 ttcagatgag ggctggcagg ggcagcttgg gcatatgcgaggctccgatg ggcatggggg 30720 ctttgaggat ggattctgag tgtccctgca tcgtggcagggtggcaaagg gagcatttcc 30780 aaatttcctg gctccaggat ctgtgggaga atcccactaactgtcagggt gacaacctcg 30840 ggtagacatg tctgtgccct gccccgtgcc ctcagccttcctgttaagag cacaccagct 30900 ggatttgcaa ctcccagcgc ctgcacccaa tgggctttctctggcctctg gagcccacat 30960 tgcccctgca tgtggcaggc tgcaagtgtc acagccaccagctcttccat tcctcaacaa 31020 tgactgtggg taaatagccc aggagcgtcc ccctcctgggatggttctga ggtgcgtgtg 31080 cccagtggct ccctgagttg ccagcaggat taagtgccagtagccctagt ggtcagctgc 31140 ttgataacac cctgcttcct ggctgctccc ccagtcccatctggtgtgtt ctgggatcat 31200 ctcccaaaga aactgcttac acttgaagcc ttgtctgaggtctgtttcta ggggaattca 31260 gatgacgata attatgcttc aggaaagcct aaattttctgcttttctctc ccctacccaa 31320 atcaggactt ttctggacac acacaccctg tggcaacctttcagcccagc agaccagagt 31380 ccgtgaatga cttgttcctc tgtccccaaa aggaactgaccagaggggtc aggccgacgc 31440 ctcgagtcag ggccccagcc acccaacaga caagatggaagaaggacctt gcagaggacg 31500 aagaggagga ggatgaggag gacacagaag atggcgtcagcttccagccc tacattgaac 31560 caccttcttt cctggggcaa gagcaccagg ctccagggcactcggaggct ggtggggtgg 31620 actcagggag gcccagggct cctctggtcc caagcgaaggctcctctgct tgggattctt 31680 cagacagaag ctgggccagc actgtggact cctcctgggacagggctggg tcctctggct 31740 atttggctga gaaggggcca ggccaagggc cgggtggggatgggcaccaa gaatctctcc 31800 caccacctga attctccaag gactcgggtt tcctggaagagctcccagaa gataacctct 31860 cctcctgggc cacctggggc accttaccac cggagccgaatctggtccct gggggacccc 31920 cagtttctct tcagacactg accttctgct gggaaagcagccctgaggag gaagaggagg 31980 cgagggaatc agaaattgag gacagcgatg cgggcagctggggggctgag agcacccaga 32040 ggaccgagga caggggccgg acattggggc attacatggccaggtgagct gtcccccgac 32100 atcccaccga atctgatgct gctgctgcct ttgcaaggactactgggctt cccaagaaac 32160 tcaagagcct ccgtacctcc cctgggcggc ggaggggcattgcacttccg ggaagcccac 32220 ctagcggctg tttgcctgtc gggctgagca ataagatgcccctccctcct gtgacccgcc 32280 ctctttaggc tgagctataa gaggggtgga cacagggtgggctgaggtca gaggttggtg 32340 gggtgtcatc acccccattg tccctagggt gacaggccagggggaaaaat tatccccgga 32400 caacatgaaa caggtgaggt caggtcactg cggacatcaagggcggacac caccaagggg 32460 ccctctggaa cttgagacca ctggaggcac acctgctatacctcatgcct ttcccagcag 32520 ccactgaact cccccatccc agggctcagc ctcctgattcatgggtcccc tagttaggcc 32580 cagataaaaa tccagttggc tgagggtttt ggatgggaagggaagggtgg ctgtcctcaa 32640 atcctggtct ttggagtcat ggcactgtac ggttttagtgtcagacagac cggggttcaa 32700 atcccagctc tgctcttcac tggttgtatg atcttggggaagacatcttc cttctctgcc 32760 tcggcttcct catctgcagc tacgcctggg tgtggtgagggttctagggg atctcagatg 32820 tgtgtagcac ggagcctgct gtgtcctggg tgctctctacgtggtggccg gtagaattct 32880 ccatctatcc aggctccagg agacccctgg gcatctcccacctgtggccc ctaaacccag 32940 agtgactgag agcacttacc attcagcttg tctcatccccagtctacctc cttccttcta 33000 ccctcactgc ctcccagtca ggagagtgag ctctcagaagccagagcccc acccaagggg 33060 accctggtct ctccgccttc acctagcaat gggaaccctgcttcccaggg gaggaaccaa 33120 ctgctccacc ttctagggac ccagtttgtt ggagtaggacagtaacatgg caggaatcgg 33180 acttctgggc ctgtaatccc agtttggatg gcacgttagactcttggttg accgttgtgg 33240 tccttagaag tcccattctc ccttccagtt atgagaaaccaatgccttct agattcaggt 33300 gactatcctt acctgggggt gctgatgcat cctcagttaacctacaccca cctgaatata 33360 gatgagcgta gctgagtttt cacccgtagg accgaagtgttttgtggtgg agtatctgaa 33420 caaccttggc tctgtggcca ttcaacctgc caggactaacatttctggat ttgtgaagaa 33480 gggatcttca aagccattga acccacagag ctgtgttgctttaaagccac cacaagggta 33540 cagcattaaa tggcagaact ggaaaagctt cttagggcatctcatccagg gattctcaaa 33600 ccatgtcccc cagaggcctt gggctgcagt tgcagggggcgccatggggc tataggagcc 33660 tcccactttc accagagcag cctcactgtg ccctgattcacacactgtgg ctttccacgt 33720 gaggttttgt ttagagggat ccactactca agaaaaagttagcaaaccac tccttttgtt 33780 gcaaaggagc tgaggtcaag ggtggcaaag gcacttgtccaaggtcgccc agcagtgctg 33840 ctctgatgac ttgtgcacat ccccaagggt aagagcttcgatctctgcac agccgggcca 33900 acctctgacc ccttgtccat gtcagtaaaa tatgaaggtcacagccagga tttctaaggg 33960 tcaggaggcc ttcaccgctg ctggggcaca cacacacacatgcatacaca catacgacac 34020 acacctgtgt ctccccaggg gttttccctg cagtgaggcttgtccagatg attgagccca 34080 ggagaggaag aacaaacaaa ctacggagct ggggagggctgtggcttggg gccagctccc 34140 agggaaattc ccagacctgt accgatgttc tctctggcaccagccgagct gcttcgtgga 34200 ggtaacttca aaaaagtaaa agctatcatc agcatcatcttagacttgta tgaaataacc 34260 actccgtttc tattcttaaa ccttaccatt tttgttttgttttgtttttt tgagtcggag 34320 ttttgttctt gttgcctagg ctggagtgca gtggtgcgatctcggctcac tgcaacctcc 34380 acctcccggg ttcaagtgat tctcctgcct cagcctcccaagtagctggg attacaggca 34440 cccgccacca cacctggcta atttttttgt atttttagtagagatggggt ttcaccatgt 34500 tggccaggct ggtctcgaac tcctgacctc aggtgatccgcccgcctcgg cctcccaaag 34560 tgctgggatt acaggcgtga gccaccgcgc ccagccaaaccttactattt ttttaaagaa 34620 ttttttccag agtttaattt ctgacatagc ttaagttttccagtaactct aaactccatc 34680 tcctttatcg tcattaagtc attcacaaaa agccaggagaagcatttgga aagggcatga 34740 taatcagtat aataatt 34757 23 27 DNAArtificial Ax5-1 oligonucleotide PCR primer 23 gctgcaggcc gctccagggaggccccg 27 24 29 DNA Artificial Ax3-1 oligonucleotide PCR primer 24ccaggtattc ggactccacc cagggggac 29 25 231 PRT Homo sapiens 25 Met MetPro Lys His Cys Phe Leu Gly Phe Leu Ile Ser Phe Phe Leu 1 5 10 15 ThrGly Val Ala Gly Thr Gln Ser Thr His Glu Ser Leu Lys Pro Gln 20 25 30 ArgVal Gln Phe Gln Ser Arg Asn Phe His Asn Ile Leu Gln Trp Gln 35 40 45 ProGly Arg Ala Leu Thr Gly Asn Ser Ser Val Tyr Phe Val Gln Tyr 50 55 60 LysIle Tyr Gly Gln Arg Gln Trp Lys Asn Lys Glu Asp Cys Trp Gly 65 70 75 80Thr Gln Glu Leu Ser Cys Asp Leu Thr Ser Glu Thr Ser Asp Ile Gln 85 90 95Glu Pro Tyr Tyr Gly Arg Val Arg Ala Ala Ser Ala Gly Ser Tyr Ser 100 105110 Glu Trp Ser Met Thr Pro Arg Phe Thr Pro Trp Trp Glu Thr Lys Ile 115120 125 Asp Pro Pro Val Met Asn Ile Thr Gln Val Asn Gly Ser Leu Leu Val130 135 140 Ile Leu His Ala Pro Asn Leu Pro Tyr Arg Tyr Gln Lys Glu LysAsn 145 150 155 160 Val Ser Ile Glu Asp Tyr Tyr Glu Leu Leu Tyr Arg ValPhe Ile Ile 165 170 175 Asn Asn Ser Leu Glu Lys Glu Gln Lys Val Tyr GluGly Ala His Arg 180 185 190 Ala Val Glu Ile Glu Ala Leu Thr Pro His SerSer Tyr Cys Val Val 195 200 205 Ala Glu Ile Tyr Gln Pro Met Leu Asp ArgArg Ser Gln Arg Ser Glu 210 215 220 Glu Arg Cys Val Glu Ile Pro 225 23026 27 DNA Artificial Ax3-2 oligonucleotide PCR primer 26 ttggttcccgcacactcttc cacttcg 27 27 130 PRT Homo sapiens 27 Met Met Pro Lys His CysPhe Leu Gly Phe Leu Ile Ser Phe Phe Leu 1 5 10 15 Thr Gly Val Ala GlyThr Gln Ser Thr His Glu Ser Leu Lys Pro Gln 20 25 30 Arg Val Gln Phe GlnSer Arg Asn Phe His Asn Ile Leu Gln Trp Gln 35 40 45 Pro Gly Arg Ala LeuThr Gly Asn Ser Ser Val Tyr Phe Val Gln Tyr 50 55 60 Lys Ile Tyr Gly GlnArg Gln Trp Lys Asn Lys Glu Asp Cys Trp Gly 65 70 75 80 Thr Gln Glu LeuSer Cys Asp Leu Thr Ser Glu Thr Ser Asp Ile Gln 85 90 95 Glu Pro Tyr TyrGly Arg Val Arg Ala Ala Ser Ala Gly Ser Tyr Ser 100 105 110 Glu Trp SerMet Thr Pro Arg Phe Thr Pro Trp Trp Glu Arg Ala Lys 115 120 125 Gly Leu130 28 263 PRT Homo sapiens 28 Met Met Pro Lys His Cys Phe Leu Gly PheLeu Ile Ser Phe Phe Leu 1 5 10 15 Thr Gly Val Ala Gly Thr Gln Ser ThrHis Glu Ser Leu Lys Pro Gln 20 25 30 Arg Val Gln Phe Gln Ser Arg Asn PheHis Asn Ile Leu Gln Trp Gln 35 40 45 Pro Gly Arg Ala Leu Thr Gly Asn SerSer Val Tyr Phe Val Gln Tyr 50 55 60 Lys Ile Met Phe Ser Cys Ser Met LysSer Ser His Gln Lys Pro Ser 65 70 75 80 Gly Cys Trp Gln His Ile Ser CysAsn Phe Pro Gly Cys Arg Thr Leu 85 90 95 Ala Lys Tyr Gly Gln Arg Gln TrpLys Asn Lys Glu Asp Cys Trp Gly 100 105 110 Thr Gln Glu Leu Ser Cys AspLeu Thr Ser Glu Thr Ser Asp Ile Gln 115 120 125 Glu Pro Tyr Tyr Gly ArgVal Arg Ala Ala Ser Ala Gly Ser Tyr Ser 130 135 140 Glu Trp Ser Met ThrPro Arg Phe Thr Pro Trp Trp Glu Thr Lys Ile 145 150 155 160 Asp Pro ProVal Met Asn Ile Thr Gln Val Asn Gly Ser Leu Leu Val 165 170 175 Ile LeuHis Ala Pro Asn Leu Pro Tyr Arg Tyr Gln Lys Glu Lys Asn 180 185 190 ValSer Ile Glu Asp Tyr Tyr Glu Leu Leu Tyr Arg Val Phe Ile Ile 195 200 205Asn Asn Ser Leu Glu Lys Glu Gln Lys Val Tyr Glu Gly Ala His Arg 210 215220 Ala Val Glu Ile Glu Ala Leu Thr Pro His Ser Ser Tyr Cys Val Val 225230 235 240 Ala Glu Ile Tyr Gln Pro Met Leu Asp Arg Arg Ser Gln Arg SerGlu 245 250 255 Glu Arg Cys Val Glu Ile Pro 260 29 560 PRT Bos taurus 29Met Leu Ala Leu Leu Gly Ala Thr Thr Leu Met Leu Val Ala Gly Arg 1 5 1015 Trp Val Leu Pro Ala Ala Ser Gly Glu Ala Asn Leu Lys Pro Glu Asn 20 2530 Val Glu Ile His Ile Ile Asp Asp Asn Phe Phe Leu Lys Trp Asn Ser 35 4045 Ser Ser Glu Ser Val Lys Asn Val Thr Phe Ser Ala Asp Tyr Gln Ile 50 5560 Leu Gly Thr Asp Asn Trp Lys Lys Leu Ser Gly Cys Gln His Ile Thr 65 7075 80 Ser Thr Lys Cys Asn Phe Ser Ser Val Glu Leu Glu Asn Val Phe Glu 8590 95 Lys Ile Glu Leu Arg Ile Arg Ala Glu Glu Gly Asn Asn Thr Ser Thr100 105 110 Trp Tyr Glu Val Glu Pro Phe Val Pro Phe Leu Glu Ala Gln IleGly 115 120 125 Pro Pro Asp Val His Leu Glu Ala Glu Asp Lys Ala Ile IleLeu Ser 130 135 140 Ile Ser Pro Pro Gly Thr Lys Asp Ser Ile Met Trp AlaMet Asp Arg 145 150 155 160 Ser Ser Phe Arg Tyr Ser Val Val Ile Trp LysAsn Ser Ser Ser Leu 165 170 175 Glu Glu Arg Thr Glu Thr Val Tyr Pro GluAsp Lys Ile Tyr Lys Leu 180 185 190 Ser Pro Glu Ile Thr Tyr Cys Leu LysVal Lys Ala Glu Leu Arg Leu 195 200 205 Gln Ser Arg Val Gly Cys Tyr SerPro Val Tyr Cys Ile Asn Thr Thr 210 215 220 Glu Arg His Lys Val Pro SerPro Glu Asn Ile Gln Ile Asn Ala Asp 225 230 235 240 Asn Gln Ile Tyr ValLeu Lys Trp Asp Tyr Pro Tyr Glu Asn Ala Thr 245 250 255 Phe Gln Ala GlnTrp Leu Arg Ala Phe Phe Lys Lys Ile Pro Gly Asn 260 265 270 His Ser AspLys Trp Lys Gln Ile Pro Asn Cys Glu Asn Val Thr Ser 275 280 285 Thr HisCys Val Phe Pro Arg Glu Val Ser Ser Arg Gly Ile Tyr Tyr 290 295 300 ValArg Val Arg Ala Ser Asn Gly Asn Gly Thr Ser Phe Trp Ser Glu 305 310 315320 Glu Lys Glu Phe Asn Thr Glu Met Lys Thr Ile Ile Phe Pro Pro Val 325330 335 Ile Ser Val Lys Ser Val Thr Asp Asp Ser Leu His Val Ser Val Gly340 345 350 Ala Ser Glu Glu Ser Glu Asn Met Ser Val Asn Gln Leu Tyr ProLeu 355 360 365 Ile Tyr Glu Val Ile Phe Trp Glu Asn Thr Ser Asn Ala GluArg Lys 370 375 380 Val Leu Glu Lys Arg Thr Asn Phe Ile Phe Pro Asp LeuLys Pro Leu 385 390 395 400 Thr Val Tyr Cys Val Lys Ala Arg Ala Leu IleGlu Asn Asp Arg Arg 405 410 415 Asn Lys Gly Ser Ser Phe Ser Asp Thr ValCys Glu Lys Thr Lys Pro 420 425 430 Gly Asn Thr Ser Lys Thr Trp Leu IleVal Gly Thr Cys Thr Ala Leu 435 440 445 Phe Ser Ile Pro Val Val Ile TyrVal Val Ser Val Phe Leu Arg Cys 450 455 460 Val Lys Tyr Val Phe Phe ProSer Ser Lys Pro Pro Ser Ser Val Asp 465 470 475 480 Glu Tyr Phe Ser AspGln Pro Leu Arg Asn Leu Leu Leu Ser Thr Ser 485 490 495 Glu Glu Gln ThrGlu Arg Cys Phe Ile Ile Glu Asn Ala Ser Ile Ile 500 505 510 Thr Glu IleGlu Glu Thr Asp Glu Ile Asp Glu Val His Lys Lys Tyr 515 520 525 Ser SerGln Thr Ser Gln Asp Ser Gly Asn Tyr Ser Asn Glu Asp Glu 530 535 540 AsnSer Gly Ser Lys Ile Ser Glu Glu Phe Pro Gln Gln Asp Ser Val 545 550 555560 30 560 PRT Bos taurus 30 Met Leu Ala Leu Leu Gly Ala Thr Thr Leu MetLeu Val Ala Gly Arg 1 5 10 15 Trp Val Leu Pro Ala Ala Ser Gly Glu AlaAsn Leu Lys Pro Glu Asn 20 25 30 Val Glu Ile His Ile Ile Asp Asp Asn PhePhe Leu Lys Trp Asn Ser 35 40 45 Ser Ser Glu Ser Val Lys Asn Val Thr PheSer Ala Asp Tyr Gln Ile 50 55 60 Leu Gly Thr Asp Asn Trp Lys Lys Leu SerGly Cys Gln His Ile Thr 65 70 75 80 Ser Thr Lys Cys Asn Phe Ser Ser ValGlu Leu Glu Asn Val Phe Glu 85 90 95 Lys Ile Glu Leu Arg Ile Arg Ala GluGlu Gly Asn Asn Thr Ser Thr 100 105 110 Trp Tyr Glu Val Glu Pro Phe ValPro Phe Leu Glu Ala Gln Ile Gly 115 120 125 Pro Pro Asp Val His Leu GluAla Glu Asp Lys Ala Ile Ile Leu Ser 130 135 140 Ile Ser Pro Pro Gly ThrLys Asp Ser Ile Met Trp Ala Met Asp Arg 145 150 155 160 Ser Ser Phe ArgTyr Ser Val Val Ile Trp Lys Asn Ser Ser Ser Leu 165 170 175 Glu Glu ArgThr Glu Thr Val Tyr Pro Glu Asp Lys Ile Tyr Lys Leu 180 185 190 Ser ProGlu Ile Thr Tyr Cys Leu Lys Val Lys Ala Glu Leu Arg Leu 195 200 205 GlnSer Arg Val Gly Cys Tyr Ser Pro Val Tyr Cys Ile Asn Thr Thr 210 215 220Glu Arg His Lys Val Pro Ser Pro Glu Asn Ile Gln Ile Asn Ala Asp 225 230235 240 Asn Gln Ile Tyr Val Leu Lys Trp Asp Tyr Pro Tyr Glu Asn Ala Thr245 250 255 Phe Gln Ala Gln Trp Leu Arg Ala Phe Phe Lys Lys Ile Pro GlyAsn 260 265 270 His Ser Asp Lys Trp Lys Gln Ile Pro Asn Cys Glu Asn ValThr Ser 275 280 285 Thr His Cys Val Phe Pro Arg Glu Val Ser Ser Arg GlyIle Tyr Tyr 290 295 300 Val Arg Val Arg Ala Ser Asn Gly Asn Gly Thr SerPhe Trp Ser Glu 305 310 315 320 Glu Lys Glu Phe Asn Thr Glu Met Lys ThrIle Ile Phe Pro Pro Val 325 330 335 Ile Ser Val Lys Ser Val Thr Asp AspSer Leu His Val Ser Val Gly 340 345 350 Ala Ser Glu Glu Ser Glu Asn MetSer Val Asn Gln Leu Tyr Pro Leu 355 360 365 Ile Tyr Glu Val Ile Phe TrpGlu Asn Thr Ser Asn Ala Glu Arg Lys 370 375 380 Val Leu Glu Lys Arg ThrAsn Phe Ile Phe Pro Asp Leu Lys Pro Leu 385 390 395 400 Thr Val Tyr CysVal Lys Ala Arg Ala Leu Ile Glu Asn Asp Arg Arg 405 410 415 Asn Lys GlySer Ser Val Ser Asp Thr Val Cys Glu Lys Thr Lys Pro 420 425 430 Gly AsnThr Ser Lys Thr Trp Leu Ile Val Gly Thr Cys Thr Ala Leu 435 440 445 PheSer Ile Pro Val Val Ile Tyr Val Val Ser Val Phe Leu Arg Cys 450 455 460Val Lys Tyr Val Phe Phe Pro Ser Ser Lys Pro Pro Ser Ser Val Asp 465 470475 480 Glu Tyr Phe Ser Asp Gln Pro Leu Arg Asn Leu Leu Leu Ser Thr Ser485 490 495 Glu Glu Gln Thr Glu Arg Cys Phe Ile Ile Glu Asn Ala Ser IleIle 500 505 510 Thr Glu Ile Glu Glu Thr Asp Glu Ile Asp Glu Val His LysLys Tyr 515 520 525 Ser Ser Gln Thr Ser Gln Asp Ser Gly Asn Tyr Ser AsnGlu Asp Glu 530 535 540 Asn Ser Gly Ser Lys Ile Ser Glu Glu Phe Pro GlnGln Asp Ser Val 545 550 555 560 31 179 PRT Homo sapiens 31 Thr Leu LeuLeu Gly Trp Leu Leu Ala Gln Val Ala Gly Ala Ala Gly 1 5 10 15 Thr ThrGlu Lys Ala Tyr Asn Leu Thr Trp Lys Ser Thr Asn Phe Lys 20 25 30 Thr IleLeu Glu Trp Glu Pro Lys Pro Ile Asn His Val Tyr Thr Val 35 40 45 Gln IleSer Thr Arg Ser Gly Asn Trp Lys Asn Lys Cys Phe Tyr Thr 50 55 60 Thr AspThr Glu Cys Asp Leu Thr Asp Glu Ile Val Lys Asp Val Thr 65 70 75 80 GlnThr Tyr Leu Ala Arg Val Leu Ser Tyr Pro Ala Arg Asn Asp Gln 85 90 95 ThrThr Gly Ser Gly Glu Glu Pro Pro Phe Thr Asn Ser Pro Glu Phe 100 105 110Thr Pro Tyr Leu Asp Thr Asn Leu Gly Gln Pro Thr Ile Gln Ser Phe 115 120125 Glu Gln Val Gly Thr Lys Leu Asn Val Thr Val Gln Asp Ala Arg Thr 130135 140 Leu Val Arg Arg Asn Gly Thr Phe Leu Ser Leu Arg Asp Val Phe Gly145 150 155 160 Lys Asp Leu Asn Tyr Thr Leu Tyr Tyr Trp Lys Ala Ser SerThr Gly 165 170 175 Lys Lys Thr 32 116 PRT Homo sapiens 32 Leu Pro LysPro Ala Asn Ile Thr Phe Leu Ser Ile Asn Met Lys Asn 1 5 10 15 Val LeuGln Trp Thr Pro Pro Glu Gly Leu Gln Gly Val Lys Val Thr 20 25 30 Tyr ThrVal Gln Tyr Phe Ile Tyr Gly Gln Lys Lys Trp Leu Asn Lys 35 40 45 Ser GluCys Arg Asn Ile Asn Arg Thr Tyr Cys Asp Leu Ser Ala Glu 50 55 60 Thr SerAsp Tyr Glu His Gln Tyr Tyr Ala Lys Val Lys Ala Ile Trp 65 70 75 80 GlyThr Lys Cys Ser Lys Trp Ala Glu Ser Gly Arg Phe Tyr Pro Phe 85 90 95 LeuGlu Thr Gln Ile Gly Pro Pro Glu Val Ala Leu Thr Thr Asp Glu 100 105 110Lys Ser Ile Ser 115 33 198 PRT Mus musculus 33 Val Leu Pro Ser Ala AlaGly Gly Glu Asn Leu Lys Pro Pro Glu Asn 1 5 10 15 Ile Asp Val Tyr IleIle Asp Asp Asn Tyr Thr Leu Lys Trp Ser Ser 20 25 30 His Gly Glu Ser MetGly Ser Val Thr Phe Ser Ala Glu Tyr Arg Thr 35 40 45 Lys Asp Glu Ala LysTrp Leu Lys Val Pro Glu Cys Gln His Thr Thr 50 55 60 Thr Thr Lys Cys GluPhe Ser Leu Leu Asp Thr Asn Val Tyr Ile Lys 65 70 75 80 Thr Gln Phe ArgVal Arg Ala Glu Glu Gly Asn Ser Thr Ser Ser Trp 85 90 95 Asn Glu Val AspPro Phe Ile Pro Phe Tyr Thr Ala His Met Ser Pro 100 105 110 Pro Glu ValArg Leu Glu Ala Glu Asp Lys Ala Ile Leu Val His Ile 115 120 125 Ser ProPro Gly Gln Asp Gly Asn Met Trp Ala Leu Glu Lys Pro Ser 130 135 140 PheSer Tyr Thr Ile Arg Ile Trp Gln Lys Ser Ser Ser Asp Lys Lys 145 150 155160 Thr Ile Asn Ser Thr Tyr Tyr Val Glu Lys Ile Pro Glu Leu Leu Pro 165170 175 Glu Thr Thr Tyr Cys Leu Glu Val Lys Ala Ile His Pro Ser Leu Lys180 185 190 Lys His Ser Asn Tyr Ser 195

What is claimed is:
 1. An isolated nucleic acid molecule encoding apolypeptide comprising an amino acid sequence at least 95% identical toamino acids 21-520 of SEQ ID NO:2.
 2. The isolated nucleic acid moleculeof claim 1, wherein said nucleic acid molecule encodes a polypeptidecomprising an amino acids 21-520 of SEQ ID NO:2.
 3. The isolated nucleicacid molecule of claim 1, wherein said nucleic acid molecule encodes apolypeptide with an amino acid sequence having one or more substitutionsrelative to the amino acid sequence of amino acids 21-520 of SEQ IDNO:2.
 4. The nucleic acid molecule of claim 9, wherein said moleculehybridizes under stringent conditions to a nucleic acid sequencecomplementary to a nucleic acid molecule comprising SEQ ID NO:1.
 5. Avector comprising the nucleic acid molecule of claim 1 and apharmaceutically acceptable carrier.
 6. A cell containing the vector ofclaim
 5. 7. A substantially purified polypeptide comprising an aminoacid sequence at least 95% identical to the amino acid sequence of aminoacids 21-520 of SEQ ID NO:2.
 8. The substantially purified polypeptideof claim 7, wherein said polypeptide comprises amino acids 21-520 of SEQID NO:2.
 9. A pharmaceutical composition comprising the polypeptide ofclaim 7 and a pharmaceutically acceptable carrier.
 10. A fusionpolypeptide comprising the polypeptide of claim 7 operably linked to anon-CRF2-13 polypeptide.
 11. The fusion polypeptide of claim 10, whereinsaid non-CRF2-13 polypeptide is selected from the group consisting of anFc region of an immunoglobulin molecules or a FLAG epitope, a HIS tag,and a MYC tag.
 12. A pharmaceutical composition comprising the fusionpolypeptide of claim 10 and a pharmaceutically acceptable carrier. 13.An antibody that binds selectively to the substantially purifiedpolypeptide of claim
 7. 14. The antibody of claim 13, wherein saidantibody is a polyclonal antibody.
 15. The antibody of claim 13, whereinsaid antibody is a monoclonal antibody.
 16. The monoclonal antibody ofclaim 13, wherein said monoclonal antibody is selected from the groupconsisting of a murine monoclonal antibody, and a humanized monoclonalantibody.
 17. A method of detecting the presence of a CRF2-13 nucleicacid molecule in a biological sample, the method comprising: contactingthe sample with a nucleic acid probe; and identifying the bound probe,if present, thereby detecting the presence of CRF2-13 nucleic acidmolecule in said sample.
 18. A method of detecting the presence of aCRF2-13 polypeptide in a sample, the method comprising: contacting thesample with a compound that selectively binds to said polypeptide underconditions allowing for formation of a complex between said polypeptideand said compound; and detecting said complex, if present, therebyidentifying said polypeptide in said sample.
 19. A method of modulatingthe activity of a CRF2-13 polypeptide, the method comprising contactinga cell sample comprising said polypeptide with a compound that binds tosaid polypeptide in an amount sufficient to modulate the activity of thepolypeptide.
 20. A method of treating or preventing a pathologicalcondition associated with a cytokine-mediated disorder, the methodcomprising administering to a subject an agent that increases levels ofa polypeptide comprising the extracellular amino acid sequence of aCRF2-13 polypeptide in an amount sufficient to alleviate or prevent thepathological condition in said subject.